KR20080011413A - Stable emulsion composition - Google Patents

Abstract

Disclosed is an emulsion composition containing a compound (A) which is stable in the acidic range and a buffer agent (B). This emulsion composition is adjusted to have a pH from about 3.7 to about 5.5.

Description

Stable Emulsifying Composition {STABLE EMULSION COMPOSITION}

The present invention relates to an emulsion composition with improved stability.

WO 99/46242 discloses compounds represented by the following formula (i), and compounds represented by the following formula (ii), or salts thereof and prodrugs thereof, in which the nitric oxide (NO) production-inhibiting effect and TNF-α, IL-1, It has an inhibitory effect on the production of inflammatory cytokines such as IL-6, and is useful as a prophylactic and therapeutic agent for diseases including heart disease, autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock, etc. States that:

[Formula i]

[Wherein R is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula: -OR ¹ wherein R ¹ optionally has a hydrogen atom or a substituent An aliphatic hydrocarbon group) or a group represented by the following formula:

Wherein R ^1b represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent, and R ^1c represents R ^1b Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ come together to form a bond,

Ring A is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, and (3) a chemical formula: -OR ^{1 in which} R ¹ represents the same meaning as mentioned above. Cycloalkene substituted by 1 to 4 substituent (s) selected from the group represented and (4) a halogen atom,

Ar represents an aromatic hydrocarbon group optionally having a substituent, and is a group represented by the following formula:

Is a group represented by the following formula:

Or a group represented by the formula:

n represents an integer of 1 to 4;

[Formula ii]

[Wherein R ^a is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula -OR ^1a (wherein R ^1a optionally has a hydrogen atom or a substituent) An aliphatic hydrocarbon group) or a group represented by the following formula:

^Wherein R ^1a has the same meaning as defined above and R ^1b is R ^1a Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a are taken together to form a bond,

Ar ^a represents an aromatic hydrocarbon group optionally having ^a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

n represents an integer of 1 to 4;

The publication also describes that oily infusions can be produced by dissolving, suspending or emulsifying the compound in vegetable oil or propylene glycol (Patent Document 1).

WO 01/10826 further discloses that a compound represented by the following formula, or a salt thereof and a prodrug thereof has a nitric oxide (NO) production-inhibiting effect and production of inflammatory cytokines such as TNF-α, IL-1, IL-6, and the like. It has a suppressive effect on the body, and is described as useful as a prophylactic and therapeutic agent for diseases including heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock and the like (Patent Document 2):

[Wherein, R ¹ is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, or formula: OR ^1a (wherein R ^1a optionally has a hydrogen atom or a substituent) An aliphatic hydrocarbon group) or a group represented by the following formula:

(Wherein R ^1b and R ^1c are the same or different from each other and represent an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

X represents a methylene group, a nitrogen atom, a sulfur atom, or an oxygen atom,

Y represents an optionally substituted methylene group or an optionally substituted nitrogen atom,

Ring A represents (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) a formula: OR ² (wherein R ² represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent) A 5-8 membered ring optionally further substituted by 1-4 substituent (s) selected from the group represented by (4) and (4) halogen atoms,

Ar represents an aromatic hydrocarbon group optionally having a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

,

,

m represents an integer of 0 to 2,

n represents an integer of 1 to 3,

The sum of m and n is 4 or less. When X is a methylene group, Y represents an optionally substituted methylene group].

[Patent Document 1] International Patent Publication No. 1999-46242 Pamphlet

[Patent Document 2] Pamphlet of International Patent Publication No. 2001-10826.

Disclosure of the Invention

It is an object of the present invention to provide an emulsion composition containing a compound that is stable in the acidic range, which is represented by the above-mentioned compounds with improved stability.

According to the specification referring to the group of compounds, compounds which are stable in the acidic range readily degrade or produce analogs in the neutral or basic range above about pH 6, and less degrade or less analogues in the acidic range (below about pH 6) Produce, and it is highly stable. In particular, compounds that are stable in the acidic range are less degraded in the acidic range when compounds in the acidic range and compounds in the neutral or basic range are stored under the same storage conditions (temperature, humidity, duration, etc.) and tested for their quality or It is a compound that produces less analogs. Although these compounds or compositions containing such compounds are stable when stored under acidic range conditions, they are difficult to store or use under such range conditions because they are unstable under the neutral or basic range. For example, when the above-mentioned compound which is stable under an acidic range is made of an emulsion composition, since the emulsion composition is generally stable in the neutral range, the range in which the compound becomes stable does not coincide with the range in which the emulsion composition becomes stable, Therefore, it was difficult to obtain a composition having excellent stability. When an emulsion composition in the neutral range is prepared by emulsifying a stable compound under the acidic range, a stable composition is not obtained due to decomposition of the compound, and when an emulsion composition in the acidic range is produced, a phospholipid contained in the emulsion composition as an emulsifier, etc. It decomposes mainly upon autoclaving or long term storage with steam, and the decomposition produces free fatty acids and lowers the pH of the emulsion composition, thereby reducing the stability of the emulsion composition. In addition, since the pH is lowered, there is a problem that the decomposition of the emulsion composition is promoted.

Washington and colleagues also disclose in [Advanced Drug Delivery Reviews 20, 131-145, 1996] that if the electrolyte component is added to the emulsion composition, the stability of the emulsion composition is reduced, thus adding electrolyte components such as buffers. It is known not to suggest.

The inventors have carried out a keen study in view of the above-mentioned problems, so that an emulsified composition containing a compound and a buffer which is adjusted to a pH of about 3.7 to about 5.5 and stable in the acidic range is unexpectedly high pressure sterilization by steam or pH during long-term storage. It was found that excellent efficacy was provided by showing extremely desirable stability without causing change. Based on this finding, further studies are carried out and the present invention is achieved.

Accordingly, the present invention provides:

[1] An emulsified composition comprising (A) a compound stable in the acidic range and (B) a buffer adjusting the pH to about 3.7 to about 5.5.

[2] The composition of [1], further comprising an anionic synthetic phospholipid as an emulsifier.

[3] The compound according to [1] or [2], wherein (A) a compound stable in an acidic range is (a) a compound represented by the following general formula (I), or (b) a compound represented by the following general formula (II), or a salt thereof Or a composition which is a prodrug thereof:

(a) a compound represented by the following formula (I):

[Wherein R is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula: -OR ¹ wherein R ¹ optionally has a hydrogen atom or a substituent An aliphatic hydrocarbon group) or a group represented by the following formula:

Wherein R ^1b represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent, and R ^1c represents R ^1b Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ come together to form a bond,

Ring A ¹ is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) the formula: -OR ¹ wherein R ¹ has the same meaning as mentioned above Cycloalkene substituted by 1 to 4 substituent (s) selected from the group represented by (4) and a halogen atom,

Ar represents an aromatic hydrocarbon group optionally having a substituent, and the group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

n represents an integer of 1 to 4;

(b) a compound represented by the following formula (II):

[Wherein, R ^{1 '} is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula -OR ^1a' (wherein R ^{1a '} is a hydrogen atom or a substituent) To an aliphatic hydrocarbon group having optionally) or a group represented by the following formula:

In which R ^{1b '} And R ^{1c ′} Are the same or different from each other, and represent an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

X represents a methylene group, a nitrogen atom, a sulfur atom, or an oxygen atom,

Y represents an optionally substituted methylene group or an optionally substituted nitrogen atom,

Ring A is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) a formula: OR ^{2 '} (wherein R ^2' is an aliphatic hydrocarbon optionally having a hydrogen atom or a substituent) Group), and a 5-8 membered ring optionally further substituted with 1-4 substituent (s) selected from (4) halogen atoms,

Ar represents an aromatic hydrocarbon group optionally having a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

,

,

m represents an integer of 0 to 2,

n 'represents an integer of 1 to 3,

the sum of m and n 'is 4 or less, provided that when X is a methylene group, Y represents an optionally substituted methylene group.

[4] The compound of formula (I), wherein [6] is (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-car Carboxylate, d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, ethyl 6- [N- (2-chlorophenyl) sulfa Moyl] cyclohex-1-ene-1-carboxylate or ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate.

[5] The composition of [1] or [2], wherein the buffer is one, two or more buffers selected from the group consisting of acetate buffer, lactate buffer, citrate buffer, and phosphate buffer.

[6] The composition of [5], wherein the acetate buffer is acetic acid and sodium acetate.

[7] The emulsion composition according to [1] or [2], wherein the buffer concentration is 100 mM or less.

[8] The composition of [1], further comprising a component selected from the group consisting of oil, emulsifier, water and combinations thereof.

[9] The composition of [8], which is of oil-in-water type.

[10] The composition according to [1] or [2], which comprises dispersed phase particles comprising a compound, an oil, and an emulsifier that is stable in an acidic range, and water in which dispersed phase particles are dispersed.

[11] The composition of [10], wherein the average particle size of the dispersed phase particles is about 0.025 to about 0.7 μm.

[12] The composition of [10], wherein the dispersed phase particles and the water in which the dispersed phase particles are dispersed are stable without phase separation.

[13] The composition of [9], which contains no free oil-drops that are visually identifiable.

[14] The composition of [8], wherein the oil is vegetable oil.

[15] The composition of [14], wherein the vegetable oil is soybean oil.

[16] The composition of [8], wherein the emulsifier is a phospholipid.

[17] The composition of [16], wherein the phospholipid is egg yolk lecithin or phosphatidylglycerol.

[18] The composition of [2], wherein the anionic synthetic phospholipid is phosphatidylglycerol.

[19] The composition of [8], wherein the oil is in a proportion of about 1 to about 30% by weight of the total composition.

[20] The composition of [8], wherein the emulsifier is in a fraction of about 0.1 to about 10% (W / V) of the total composition.

[21] The composition of [17] or [18], wherein the phosphatidylglycerol is dimyristoylphosphatidylglycerol.

[22] The composition of [8], further comprising soybean oil, egg yolk lecithin, glycerin, and water.

[23] The composition for injection according to [1] or [2].

[24] The composition of [1] or [2], wherein the compound that is stable in the acidic region is present in a fraction of about 0.001% to about 95% by weight of the total composition.

[25] A process for preparing an emulsion composition comprising (A) a compound stable in an acidic range and (B) a buffer, the method comprising adjusting the pH of the emulsion composition to a range of about 3.7 to about 5.5.

[26] The method of [25], wherein the emulsion composition further comprises an anionic synthetic phospholipid as an emulsifier.

[27] The method of [25], wherein the stability of the pH of the emulsion composition and the particle size of the dispersed phase particles are improved during autoclave sterilization.

[28] A method of stabilizing an emulsion composition for a long time, comprising adjusting the pH of the emulsion composition comprising (A) a compound stable in the acidic range, and (B) a buffer.

[29] The method of [28], further comprising adding an anionic synthetic phospholipid as an emulsifier to the emulsion composition.

The present invention further provides the following.

[30] The composition of [1] or [2], which is a nitric oxide and / or cytokine production inhibitor, or a TLR signal inhibitor.

[31] The method of [1] or [2], wherein heart disease, autoimmune disease, sepsis, septic shock, severe sepsis, organ failure, ichorrhemia, endotoxin shock, shock, inflammatory disease, central nervous system disease or infection A composition that is an agent for treating a disease.

[32] Heart disease, autoimmune disease, sepsis, septic shock, severe sepsis, organ failure, sepsis comprising administering a pharmaceutically effective amount of the composition of [1] or [2] to a mammal in need thereof; ichorrhemia), endotoxin shock, shock, inflammatory diseases, central nervous system diseases or infectious diseases.

[33] Preparation of preparation for the prevention or treatment of heart disease, autoimmune disease, sepsis, septic shock, severe sepsis, organ failure, ichorrhemia, endotoxin shock, shock, inflammatory disease, central nervous system disease or infectious disease Use of the composition of [1] or [2] for the following.

[34] The compound of [3], wherein in formula (I), R is

(1) (as oxide random) (i) C _{1 -4} alkyl, hydroxy, oxo and C _{1 -4} any nitrogen atom being optionally substituted by 1 to 3 substituent (s) selected from alkoxy, oxygen atom and one to four 5- to 8-membered ring group containing a hetero atom or a condensed ring group selected from a sulfur atom, (ii) oxo group, (iii) hydroxyl groups, (iv) C _{1 -6} alkoxy group, (v) C _{3 -10} cycloalkyloxy groups, (vi) C _{6 -10} aryloxy group, (vii) C _{7 -19} aralkyl oxy group, (viii) C _{1 -4} alkyl, hydroxy, oxo and C ₁ (any oxide), optionally a nitrogen atom which is substituted by 1 to 3 substituent (s) selected from alkoxy _-4, 5- to 8 containing from 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom membered cyclic group, or a condensed ring-oxy group, (ix) C _{1 -6} alkylthio group (sulfur atom may be oxidized), (x) C _{3 -10} cyclo alkylthio group (sulfur atom may be oxidized) , (xi) C _{6 -10} aryl come tea (sulfur atom may be oxidized), (xii) C _{7 -19} aralkyl thio group (sulfur atom may be oxidized), (xiii) C _{1 -4} alkyl, hydroxy, oxo, and C ₁ (being optionally oxidized), any nitrogen atom which is substituted by 1 to 3 substituent (s) selected from alkoxy _-4, 5- to containing 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom 8-membered cyclic group or a condensed ring-coming T, (xiv) C _{1 -4} alkyl, hydroxy, oxo and optionally substituted, a nitrogen atom with one to three substituent (s) selected from a C _{1 -4} alkoxy ( any oxidation search), an oxygen atom and to 5 containing 1 to 4 heteroatoms selected from sulfur atoms 8-membered ring group or a condensed ring-sulfinyl group, (xv) C _{1 -4} alkyl, hydroxy, oxo and (as oxide random) any nitrogen atom being optionally substituted by C _{1 -4} alkoxy of 1 to 3 substituent (s) selected from the mountain 5- to 8-membered ring groups or condensed ring-sulfonyl groups containing 1 to 4 hetero atoms selected from atoms and sulfur atoms, (xvi) nitro groups, (xvii) halogen atoms, (xviii) cyano groups, ( xix) carboxyl group, (xx) C _{1 -10} alkoxy-carbonyl group, (xxi) C _{3 -6} cycloalkyloxy-carbonyl group, (xxii) C _{6 -10} aryloxy-carbonyl group, (xxiii) C _{7 -19} aralkyloxy -carbonyl group, (xxiv) C _{1 -4} alkyl, hydroxy, oxo and C _{1 -4} (random search oxide) optionally, a nitrogen atom which is substituted by 1 to 3 substituent (s) selected from alkoxy, oxygen atom and sulfur 5- to 8-membered containing 1 to 4 heteroatoms selected from membered ring group or a condensed ring-oxycarbonyl group, (xxv) C _{6 -10} aryl group, (xxvi) C _1-6 alkanoyl group, ( xxvii) C _{3 -5} alkenyl noilgi, (xxviii) C _{6 -10} aryl-carbonyloxy group, (xxix) C _{2 -6} alkanoyloxy group, (xxx) C _{3 -5} alkenyl Russo Group, (xxxi) C _{1 -4} alkyl, phenyl, C _1-7 acyl and C _{1 -4} alkoxy-carbamoyl group, or cyclic optionally substituted by one or two substituent (s) selected from phenylamino group , (xxxii) C _{1 -4} thiocarbamoyl group, (xxxiii) C _{1 -4} with one or two substituents selected from alkyl and phenyl optionally substituted by one or two substituent (s) selected from alkyl, and phenyl carbamoyloxy group optionally substituted by a (s), (xxxiv) C _{1 -6} alkanoylamino group, (xxxv) C _{6 -10} aryl-carbonylamino group, (xxxvi) C _{1 -10} alkoxy-carboxamide group , (xxxvii) C _{6 -10} aryloxy-carboxamide group, (xxxviii) C _{7 -19} aralkyloxy-carboxamide group, (xxxix) C _{1 -10} alkoxy-carbonyloxy group, (xxxx) C _6-10 aryloxy-carbonyloxy group, (xxxxi) C _{7 -19} aralkyloxy-carbonyloxy group, (xxxxii) C _{3 -10} cycloalkyloxy-carbonyloxy group, (xxxxiii) C _{1 -4} ureido group optionally substituted by 1 to 3 substituent (s) selected from an alkyl group and a phenyl group, and (xxxxiv) the above-mentioned (i) - is selected from the group consisting of (xxxxiii) 1 to 4 substituents an optionally C _{6 -10} group having from 1 to 4 substituents selected from the group consisting of (hereinafter substituent group a) optionally having an aryl (1) linear or branched C _{1 -20} alkyl group, (2) C _{3 -10} cycloalkyl group , (3) _-12 C ₄ cycloalkyl group, (4) a lower (C _{3 -6)} alkenyl group or (5) a lower (C _{3 -6)} alkynyl group (wherein the substituent selected from substituent group A, (1 ) linear or branched (C _{1 -20)} alkyl group, (2) C _{3 -10} cycloalkyl group, (3) _-12 C ₄ cycloalkyl group, (4) a lower (C _{3 -6)} alkenyl group or (5) lower-(C _{3 -6)} 1,2,3,4- tetrahydro together with alkynyl groups, 1 to 4 substituents selected from substituent group a or a naphthyl group optionally hydrochloride May form a group carry),

(2) a halogen atom, C _{1 -4} alkyl, C _{1 -4} alkoxy groups, C _{1 -4} alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, C _{1 -4} alkanoylamino group, C _{3 - 6} cycloalkyl group, C _{6, -10} aryl group, a halogeno-C _{1 -4} alkyl group, a halogeno-C _{1 -4} alkoxy groups, C _{1 -4} alkylthio, C _{1 -4} alkylsulfonyl group, C _{1 -4} alkanoyl group, a 5-membered aromatic heterocyclic group, carbamoyl group, C _1-4 alkyl-carbamoyl group, C _{1 -4} alkoxy-carbonyl -C _{1 -4} alkyl-carbamoyl group and 1,3-dia silgu No gavel -C ₁ C _{6 -14} aromatic hydrocarbon having from 1 to 5 substituents selected from the group consisting of optionally _-4 alkyl group,

(3) C _{1 -4} alkyl, hydroxy, oxo and C _{1 -4} which having from 1 to 3 substituents selected from the group consisting of alkoxy, optionally, a nitrogen atom (optionally oxidized search), selected from an oxygen atom and a sulfur atom 5- to 8-membered ring groups or condensed ring groups containing 1 to 4 hetero atoms,

(4) a group (wherein in the formula -OR ^1, R ¹ is (i) <1> linear or branched C _{1 -20} having 1 to 4 substituents selected from a hydrogen atom or (ii) the substituent group A optionally alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> lower (C _{3 -6)} alkynyl group (wherein , substituents selected from substituent group A or <1> linear or branched C _{1 -20} alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> lower (C _{3 -6)} alkynyl group with the substituent group a 1 to 4 substituents optionally 1,2,3,4-tetrahydro-indazol-naphthyl group or having a selected from carbonyl May form a group), or

(5) a group of the formula:

{Wherein, R ^1b is (i) hydrogen atom or (ii) a substituent group having 1 to 4 substituents selected from optionally A <1> linear or branched C _{1 -20} alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> lower (C _{3 -6)} alkynyl group (wherein the substituent selected from substituent group A, <1> linear or branched C _1-20 alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> is lower (C _{3 -6)} alkynyl group that together, may form the substituent group a 1 to 4 substituents optionally an 1,2,3,4-tetrahydro-naphthyl, or indanyl which is selected from a), R ^1c R ^1b are the same or different and, (i) hydrogen atom or (ii) a substituent having 1 to 4 substituents selected from the group a, optionally <1> linear or branched C _{1 -20} alkyl group, <2> C _3-10 cycles The alkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _3-6) alkenyl group or <5> lower (C _{3 -6)} alkynyl group (wherein the substituent selected from Substituent group A, <1> linear or branched C _{1 -20} alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> lower (C _{3 -6)} alkynyl group that together, may form the substituent group a 1 to 4 substituents optionally an 1,2,3,4-tetrahydro-naphthyl, or indanyl which is selected from a)} and Im ,

R ⁰ is a hydrogen atom, a linear or branched C _{1 -20} alkyl, C _{3 -10} cycloalkyl, C _{4 -12} cycloalkyl alkyl group, a lower (C _{3 -6)} alkenyl or lower (C _{3 -6)} alkynyl Or R and R ⁰ are taken together to form a bond,

Ring A ¹ tooth

, <1> having (1) from 1 to 4 substituents selected from Substituent group A, optionally a linear or branched C _{1 -20} alkyl group, <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkyl alkyl group, <4> lower (C _{3 -6)} alkenyl group or <5> lower _{(3 -6} C) alkynyl group (wherein the substituent selected from substituent group A or <1> linear or branched C _{1 -20} alkyl <2> C _{3 -10} cycloalkyl group, <3> C _{4 -12} cycloalkylalkyl group, <4> with a lower (C _{3 -6)} alkenyl group or <5> lower (C _{3 -6)} alkynyl group, Can form 1,2,3,4-tetrahydronaphthyl group or indanyl group having 1 to 4 substituents selected from substituent group A),

(2) a halogen atom, C _{1 -4} alkyl, C _{1 -4} alkoxy groups, C _{1 -4} alkoxy-carbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, C _{1 -4} alkanoylamino group, C _{3 - 6} cycloalkyl group, C _{6 -10} aryl group, a halogeno-C _{1 -4} alkyl group, a halogeno-C _{1 -4} alkoxy groups, C _{1 -4} alkylthio, C _{1 -4} alkylsulfonyl group, C _{1 -4} alkanoyl group, a 5-membered aromatic heterocyclic group, carbamoyl group, C _{1 -4} alkyl- carbamoyl, C _{1 -4} alkoxy-carbonyl -C _{1 -4} alkyl- carbamoyl and 1,3-dia silgu No gavel -C ₁ C _{6 -14} aromatic hydrocarbon having from 1 to 5 substituents selected from the group consisting of optionally _-4 alkyl group,

(3) a group of formula -OR ¹ wherein R ¹ is as defined above, or

(4) cycloalkene optionally substituted by 1 to 4 substituent (s) selected from halogen atoms,

Ar is halogen, C _{1 -4} alkyl, C _{1 -4} alkoxy groups, C _{1 -4} alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, a hydroxyl group, C _{1 -4} alkanoylamino group, C _{3 -6} cycloalkyl alkyl group, a C _{6 -10} aryl group, a halogeno-C _{1 -4} alkyl group, a halogeno-C _{1 -4} alkoxy groups, C _{1 -4} alkylthio, C _{1 -4} alkylsulfonyl group, C _{1 -4} alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group, C _{1 -4} alkyl-carbamoyl group, C _{1 -4} alkoxy-carbonyl -C _{1 -4} alkyl-carbamoyl group and 1,3-dia silgu no gavel -C _{1 -4} with 1 to 5 substituents selected from the group consisting of alkyl optionally C _{6 -14} composition which an aromatic hydrocarbon group.

[35] The composition of [3], wherein the compound represented by the formula (I) is (i) a compound represented by the following formula (Iaa), or (ii) a compound represented by the following formula (Ie):

[Wherein R is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula: -OR ¹ wherein R ¹ optionally has a hydrogen atom or a substituent An aliphatic hydrocarbon group) or a group represented by the following formula:

Wherein R ^1b represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent, and R ^1c represents R ^1b Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ come together to form a bond,

Ring A ² is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) the formula: -OR ¹ , wherein R ¹ has the same meaning as mentioned above Cycloalkene substituted by 1 to 4 substituent (s) selected from the group represented by (4) and a halogen atom,

Ar is an aromatic hydrocarbon group optionally having a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

n represents an integer of 1 to 4;

[Wherein R ^a is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula -OR ^1a (wherein R ^1a optionally has a hydrogen atom or a substituent) An aliphatic hydrocarbon group) or a group represented by the following formula:

^Wherein R ^1a has the same meaning as defined above and R ^1b is R ^1a Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a are taken together to form a bond,

Ar ^a represents an aromatic hydrocarbon group optionally having ^a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

,

,

n represents an integer of 1 to 4;

[36] The composition of [35], wherein the compound represented by the formula (Iaa) is a compound represented by the following formula (Ibb):

Wherein each symbol represents the same meaning as defined in [35].

[37] The composition of [35], wherein ring A ² is cycloalkene substituted with lower alkyl, phenyl or halogen, R ¹ is lower alkyl group, Ar is phenyl group optionally having a substituent, and n is 2.

[38] The composition of [35], wherein the compound represented by the formula (Ie) is a compound represented by the following formula (Ia):

[Wherein R is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, the formula: -OR ¹ wherein R ¹ optionally has a hydrogen atom or a substituent An aliphatic hydrocarbon group) or a group represented by the following formula:

Wherein R ^1b represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent, and R ^1c represents R ^1b Is the same as or different from an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent),

R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ come together to form a bond,

Ar represents an aromatic hydrocarbon group optionally having a substituent,

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

,

,

n represents an integer of 1 to 4, provided that n is 1 or 2, (i) R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, Ar is a phenyl group, or (ii) R and R ⁰ Form a bond and Ar is a phenyl group, 2-methylphenyl group, 4-bromophenyl group, 4-methoxyphenyl group or 2,6-dimethylphenyl group,

The group represented by:

Can be a group represented by:

].

].

[39] The composition of [38], wherein the compound represented by the formula (Ia) is a compound represented by the following formula (Ib):

[Wherein, R ² represents a hydrogen atom or an aliphatic hydrocarbon group, and the groups represented by R ¹ , Ar, n and the following formulas have the same meanings as defined in [38]:

Provided that when n is 1 or 2, Ar is a phenyl group, R ¹ is a hydrogen atom or an ethyl group, and R ² is a methyl group, the group represented by the following formula:

May be a group represented by the formula:

].

].

[40] The composition of [39], wherein R ¹ is a lower alkyl group optionally having a substituent.

[41] The composition of [39], wherein R ¹ is an ethyl group.

[42] The composition of [39], wherein R ² is a hydrogen atom or a lower alkyl group.

[43] The composition of [39], wherein R ² is a hydrogen atom.

[44] The composition of [39], wherein Ar is a phenyl group optionally having a substituent.

[45] The composition of [39], wherein Ar is a phenyl group substituted with halogen and / or lower alkyl.

[46] The composition of [39], wherein Ar is a group represented by the following formula:

[Wherein, R ⁴ and R ⁵ are the same as or different from each other, and represent a halogen atom or a lower alkyl group, and n represents an integer of 0 to 2].

[47] The composition of [39], wherein the halogen atom is a fluorine atom or a chlorine atom.

[48] The group represented by the following formula in [39]:

A composition which may be a group represented by the formula:

Wherein n has the same meaning as defined in [39].

[49] The composition of [39], wherein n is 1 to 3.

[50] The composition of [39], wherein R ¹ is a lower alkyl group optionally having a substituent, R ² is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having a substituent, and n is 1, 2 or 3.

[51] The composition of [39], wherein R ¹ is a lower alkyl group optionally having a substituent, R ² is a hydrogen atom, Ar is a phenyl group substituted with a halogen atom, and n is 2.

[52] The composition of [38], wherein the compound represented by the formula (Ia) is a compound represented by the following formula (Ic):

[Wherein Ar and n have the same meaning as defined in [38]].

[53] The composition of [52], wherein Ar is a phenyl group optionally having a substituent, and n is 2.

[54] The composition of [38], wherein the compound represented by the formula (Ia) is a compound represented by the following formula (Id):

[Wherein, R ¹ , R ² and Ar have the same meaning as defined in [39],

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

Provided that Ar is a phenyl group and R ¹ When it is this hydrogen atom or an ethyl group, and R <^2> is a methyl group, the group represented by following formula is:

May be a group represented by the formula:

].

].

[55] The composition of [35], wherein the compound represented by the formula (Ie) is a compound represented by the following formula (If):

[Wherein, R ^2a represents a hydrogen atom or an aliphatic hydrocarbon group, and R ^1a , Ar ^a , n and the groups represented by the following formulas are:

Meaning the same as defined in [35].

[56] The composition of [35], wherein the compound represented by the formula (Ie) is a compound represented by the following formula (Ig):

[Wherein, R ^1a , R ^2a and Ar ^a have the same meaning as defined in [55], and the group represented by the following formula:

A group represented by the following formula:

Or may be a group represented by the formula:

].

].

[57] The composition of [8], wherein the oil component is selected from the group consisting of vegetable oils, partially hydrogenated vegetable oils, monoglycerides, mixed glycerides and medium-sized chain fatty acid glycerin esters.

[58] The composition of [8], wherein the vegetable oil is selected from the group consisting of soybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil, foreskin oil and olive oil.

[59] The composition of [8], wherein the emulsifier is a phospholipid or a nonionic surfactant.

[60] The composition of [8], wherein the phospholipid is egg yolk lecithin, soy lecithin, a hydrogenated product thereof, phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, phosphatidylinositol, or phosphatidylglycerol.

[61] The composition of [8], wherein the anionic phospholipid is further contained in the emulsifier in a fraction of about 0.0001 to about 5% (W / V) of the total composition.

[62] The composition of [61], wherein the anionic phospholipid is dimyristoylphosphatidylglycerol.

[63] The composition of [8], wherein the emulsifier is contained in a proportion of about 0.1 to about 150% by weight of the oil component.

Effects of the Invention

The emulsion composition of the present invention is adjusted to about pH 3.7 to about pH 5.5 by adding a buffer. Thus, the pH of the emulsion composition and the average particle size of the dispersed phase particles therein hardly change after sterilization in an autoclave or the like, or even after long term storage, and the composition is stable. As a result, the emulsion composition of the present invention and the compound which is the active ingredient of the emulsion composition, its salt or prodrug thereof show excellent stability. Moreover, sterilization and long-term preservation of the emulsion compositions of the present invention in autoclaves and the like do not produce visible observable droplets of oil. That is, the dispersed phase particles and the water in which the dispersed phase particles are dispersed do not exhibit phase separation and are stable.

In addition, since the pH of the emulsion composition of the present invention can be adjusted to about 3.7 to about 5.5 by adding a buffer, a stable emulsion composition can be obtained according to various other conditions such as the characteristics of the emulsifier and the stability of the compound, and the like. Can be determined. Thus, even when there are other conditions that can be overcome by adjusting the pH from about 3.7 to about 5.5, such as when the stability of the emulsion composition is affected, an emulsion composition that satisfies various conditions by adopting pH adjustment is Can be obtained.

Moreover, the emulsion composition of the present invention shows long term storage stability for 24 hours. This is in excess of 18 months, which is the general duration of use of emulsified formulations.

Best mode for carrying out the invention

Hereinafter, embodiments of the present invention will be described.

The compound used in the emulsion composition of the present invention is a compound which is stable in the acidic range described above, specifically, a compound represented by formula (I) or (II), or a salt thereof or a prodrug thereof.

(A) For Compounds of Formula (I)

In the specification, R is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a group represented by the formula -OR ¹ , wherein R ¹ optionally has a hydrogen atom or a substituent Aliphatic hydrocarbon group), or a group represented by the following formula:

(Wherein, R ^1b represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent, R ^1c is the same as or different from R ^1b and represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent), or R is R ⁰ Groups together with which a bond is formed and represented by the formula -OR ^{1 in which} R ¹ represents the same meaning as defined above are preferred.

R ^a is an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a group represented by the formula -OR ^1a , wherein R ^1a optionally has a hydrogen atom or a substituent Aliphatic hydrocarbon group), or a group represented by the following formula:

(Wherein, R ^1a represents the same meaning as defined above, R ^1b and R ^1a are the same or different and each represents an aliphatic hydrocarbon group having a hydrogen atom or an optionally substituted), or R ^{0a '} Form a bond with the compound of formula -OR ^1a In the formula, R ^1a represents the same meaning as defined above.

When R and R ⁰ are combined to form a bond, the compound represented by formula (Iaa) may be represented by the following formula (Ihh):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (Icc) or the following formula (Iii):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

When R and R ⁰ are collected to form a bond, the compound represented by the formula (Ia) may be represented by the following formula (Ih):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (Ic) or the following formula (Ii):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

When R ^a and R ^0a come together to form a bond, the compound represented by formula (Ie) may be represented by the following formula (Ij):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (Ik) or the following formula (Im):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

When R is a group represented by the formula -OR ^{1 in which} R ¹ represents the same meaning as defined above, the compound represented by the formula (Iaa) may be represented by the following formula (Ibb):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (Inn) or the following formula (Ioo):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

When R is a group represented by the formula -OR ^{1 in which} R ¹ represents the same meaning as defined above, the compound represented by the formula (Ia) may be represented by the following formula (Ib):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (In) or the following formula (Io):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

When R ^a is a group represented by the formula -OR ^{1a in which} R ^1a has the same meaning as defined above, the compound represented by the formula (Ie) may be represented by the following formula (If):

Wherein each symbol represents the same meaning as defined above, specifically, it may be represented by the following formula (Ip) or the following formula (Iq):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

As the compound represented by the formula (Iaa), the compound represented by the formula (Icc) or the formula (Inn) is preferable, and as the compound represented by the formula (Ia), the compound represented by the formula (Ic) or the formula (In) is preferable, As the compound represented by the formula (Ie), the compound represented by the formula (Ik) or the formula (Ip) is preferable.

Similarly, the compound represented by the formula (Id) may be represented by the following formula (Ir) or the following formula (Is):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above, the compound represented by the formula (Ig) may be represented by the following formula (It) or the following formula (Iu):

Wherein each symbol represents the same meaning as defined above,

Wherein each symbol represents the same meaning as defined above.

As a compound represented by general formula (Id), the compound represented by general formula (Ir) is preferable, and as a compound represented by general formula (Ig), the compound represented by general formula (It) is preferable.

In the compound represented by the formula (Ia), n is 1 or 2, (i) R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, Ar is a phenyl group, or (ii) R and R ⁰ are grouped together When Ar is a phenyl group, 2-methylphenyl group, 4-bromophenyl group, 4-methoxyphenyl group or 2,6-dimethylphenyl group, the group represented by the following formula is:

It may be a group represented by the following formula:

.

.

Furthermore, n represents 1 to 4, (i) R ¹ is a lower alkyl group optionally having a hydrogen atom or a substituent, R ⁰ is a lower alkyl group optionally having a substituent, and Ar is a phenyl group optionally having a substituent, or (ii When R and R ⁰ are collected to form a bond, and Ar is a phenyl group optionally having a substituent, the group represented by the following formula:

It may be a group represented by the following formula:

.

.

In the compound represented by the formula (Ib), when n is 1 or 2, R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, the group represented by the following formula is:

It may be a group represented by the following formula:

.

.

Furthermore, when n is 1 to 4, R ¹ is a lower alkyl group optionally having a hydrogen atom or a substituent, R ⁰ is a lower alkyl group optionally having a substituent, and Ar is a phenyl group optionally having a substituent, the group represented by the following formula:

It may be a group represented by the following formula:

.

.

"Aliphatic hydrocarbon group" of "optionally substituted aliphatic hydrocarbon group" represented by R, R ^a , R ¹ , R ^1a , R ^1b , R ^1c , and "aliphatic group represented by R ⁰ , R ^0a , R ² , R ^2a As a hydrocarbon group ", an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, etc. are preferable, for example.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group and the like are preferred, and in particular, for example, lower alkyl group having 1 to 6 carbon atoms (for example, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like).

As a cycloalkyl group, a C3-C10 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc.) etc. are preferable, for example, In particular, a C3-C6 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.) etc. are preferable, for example.

As the cycloalkylalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbon atoms (for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) is preferable, and for example, for example, Preferred are cycloalkylalkyl groups having 4 to 8 carbon atoms (especially 4 to 7) (for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.).

As the alkenyl group, for example, a lower alkenyl group having 3 to 6 carbon atoms (for example, propenyl group, butenyl group, pentenyl group, etc.) is preferable, and for example, lower alkenyl group having 3 or 4 carbon atoms is preferable. (For example, propenyl group, butenyl group, etc.) etc. are preferable.

As the alkynyl group, for example, a lower alkynyl group having 3 to 6 carbon atoms (for example, a propynyl group, a butynyl group, a pentynyl group, etc.) is preferable, and for example, a lower alkynyl group having 3 or 4 carbon atoms ( For example, propynyl group, butynyl group, etc.) are preferable.

As the "substituent" of the "aliphatic hydrocarbon group optionally having substituents", for example, a heterocyclic group, an oxo group, a hydroxy group, C _{1 -6} alkoxy, C _{3 -10} (in particular, C _{3 -6)} cycloalkyl alkyloxy, C _{6 -10} aryloxy group, C _{7 -19} (in particular, C _{7 -12)} aralkyl oxy group, a heterocyclic oxy group, C _{1 -6} alkylthio group (the sulfur atom may be oxidized) , C _{3 -10} (in particular, C _{3 -6)} cycloalkyl come tea (which can be oxidized sulfur atom), C _{6 -10} aryl come tea (sulfur atom may be oxidized), C _7-19 (particularly, C _{7 - 12)} aralkyl come tea (which can be oxidized sulfur atom), coming heterocyclic tea, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a nitro group, a halogen atom, a cyano group, a carboxyl group, C _{1 -10} (particularly, C _{1 -6)} alkoxy-carbonyl group, C _{3 -6} cycloalkyloxy-carbonyl group, C _{6 -10} aryloxy-carbonyl group, C _{7 -9} (particularly, C _{7 -12)} aralkyloxy-carbonyl group, heterocyclic city Click oxycarbonyl group, C _{6 -10} aryl-carbonyl group, C _{1 -6} alkanoyl, C _{3 -5} alkenyl noilgi, C _6-10 aryl-carbonyloxy group, C _{2 -6} alkanoyloxy group, C _{3 - 5} Al Keno acryloyloxy group, a carbamoyl group, a thiocarbamoyl group, carbamoyloxy group having a substituent optionally having a substituent optionally having a substituent, optionally, C _{1 -6} alkanoylamino group, C _{6 -10} aryl-carbonyl group, C _{1 -10} (in particular, C _{1 -6)} alkoxy-carboxamide group, C _{6 -10} aryloxy-carboxamide group, C _{7 -19} (particularly, C _7-12) aralkyloxy-carboxamide group, C _{1 -10} (in particular, C _{1 -6)} alkoxy-carbonyloxy group, C _{6 -10} aryloxy-carbonyloxy group, C _{7 -19} (in particular, C _{7 -12)} aralkyloxy-carboxamide carbonyloxy group, C _{3 -10} (in particular, C _{3 -6)} cycloalkyloxy-carbonyloxy group, etc., a ureido group, C _{6 -10} aryl group optionally having substituents optionally having substituents are used.

Such substituents are substituted at substitutable positions of the "aliphatic hydrocarbon group", and the substituents are not limited to one, and may be the same or different, and may be several (2 to 4).

"C _{1 -6} alkoxy group" as, for example, methoxy, ethoxy, n- propoxy, iso-propoxy, n- butoxy group, tert- butoxy group, n- pen tilok group, a n- hexyl as this is being used, "C _{3 -10} cycloalkyloxy groups" such -1,3 time, for example, as the cyclopropyl-oxy group, cyclohexyloxy group, etc. are used, "C _{6 -10} aryloxy group", for example, phenoxy group, naphthyloxy group, etc. are used, "C _{7 -19} aralkyl-oxy group" as, for example, benzyloxy group, 1-phenylethyl oxy group, 2-phenylethyl oxy group, benzhydryl oxy group, 1-naphthyl-methyl-oxy group, etc. are used, as the "C _{1 -6} alkyl come tea (which can be oxidized sulfur atom)", such as methyl thio group, ethyl thio group, n- propyl thio, n- Import butyl tea, methyl sulfinyl group, is used, such as methyl sulfonyl group, "C _{3 -10} come cycloalkyl tea (which can be oxidized sulfur atom)" come, for example, cyclopropyl T as, Cyclohexyl silti come, cyclopentyl sulfinyl group, sulfonyl group, cyclohexyl, etc. are used, "C _{6 -10} aryl come tea (which can be oxidized sulfur atom)" as, for example, phenylthio, naphthyl tilti come, phenyl A sulfinyl group, a phenylsulfonyl group, or the like is used, and as the "C _{7 -19} aralkylthio group (a sulfur atom may be oxidized)", for example, benzylthio group, phenylethylthio group, benzhydrylthio group, benzyl a sulfinyl group, benzyl-sulfonyl group, etc. are used, "halogen atom" as, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used and the like, - as the "C _{1 -10} alkoxycarbonyl groups", for example, methoxy group, ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, a tert- butoxycarbonyl group, etc. are used, as the "C _{1 -6} cycloalkyloxy group", Example , Cyclopropyl-oxy group, a cyclopentyloxy group, a cyclohexyl oxy group, a norbornyl oxycarbonyl group and the like are used, and - as the "C _6-10 aryloxycarbonyl group", for example, phenoxy group, naphthyloxy group etc. It is used, and - as the "C _{7 -19} aralkyl-oxycarbonyl group", for example, a benzyloxycarbonyl group, benzhydryl oxy group, a 2-phenethyl oxycarbonyl group and the like are used, "C _{6 -10} aryl-carbonyl group," as the , for example, benzoyl group, naphthoyl group, a phenylacetyl group, etc. are used, "C _{1 -6} alkanoyl" as, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, blood is used, such as feet, weather, as the "C _{3 -5} alkenyl noilgi", for example, acryloyl group, a croissant noilgi agent and the like are used, and - as the "C _{6 -10} aryl carbonyloxy group", for example, Benzoyloxy group , Naphthoquinone-yloxy group, a phenyl-acetoxy group, etc. are used, "C _{2 -6} alkanoyloxy group" as, for example, acetoxy, propionyloxy oxy group, butynyl group rilok, valerian oxy group, pivaloyloxy group, etc. are used, as the "C _{3 -5} al Keno acryloyloxy group", for example, acryloyloxy group of acrylic, chroman teuno yloxy group and the like are used.

As the "carbamoyl group optionally having substituents", for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), phenyl, C _{1 -7} acyl (e.g., acetyl, propionyl, benzoyl, etc. ), C _{1 -4} alkoxy-phenyl (e.g., methoxyphenyl, etc.) which may be substituted with 1 or 2 substituents selected from, such as a carbamoyl group or a cyclic amino group is used, such as, specifically, Carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-phenylcarbamoyl group, N-acetyl carbamoyl group , N-benzoylcarbamoyl group, N- (p-methoxyphenyl) carbamoyl group, 1-pyrrolidinylcarbonyl group, piperizinocarbonyl group, 1-piperazinylcarbonyl group, morpholinocarbonyl group and the like are used. "Thiocarbamoyl group optionally having substituents" as, for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from phenyl, etc. A diary is used, and a thiocarbamoyl group, an N-methylthio carbamoyl group, an N-phenylthiocarbamoyl group, etc. are used specifically ,. As the "carbamoyloxy group optionally having substituents", for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), carbamoyl which may be substituted with 1 or 2 substituents selected from phenyl, etc. together An oxy group is used, and specifically, a carbamoyloxy group, N-methyl carbamoyloxy group, N, N- dimethylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-phenylcarbamoyl jade is mentioned, for example. The timing is used.

As the "C _{1 -6} alkanoylamino group", for example, acetoamide group, a propionamide group, butyryl amide group, an amide group valerolactone, such as blood immediately amide group is used, "C _{6 -10} aryl-carbonyl amino group "as, for example, a benzamide group, a naphthoyl amide group, an imide group such as phthalimide is used," C _{1 -10} alkoxy-as-carboxamide group ", for example, a methoxy-carboxamide (CH ₃ OCONH-) group, an ethoxy-carboxamide group, a tert- butoxy-carboxamide group, etc. are used, the "C _{6 -10} aryloxy-carboxamide group" as, for example, phenoxy-carboxamide ( C ₆ H ₅ OCONH-) group and the like are used, and as the "C _{7 -19} aralkyloxy-carboxamide group", for example, benzyloxycarboxamide (C ₆ H ₅ CH ₂ OCONH-) group, benz Hi drill aryloxy-carboxamide group, etc. are used, "C _{1 -10} alkoxy-carbonyloxy group" as, for example, a methoxy carbonyloxy group, an ethoxy Carbonyloxy group, n-propoxycarbonyloxy group, isopropoxycarbonyloxy group, n-butoxycarbonyloxy group, tert-butoxycarbonyloxy group, n-pentyloxycarbonyloxy group, n -hexyloxy group optionally Brassica Viterbo and the like are used, "C _{6 -10} aryloxy-carbonyloxy group" as, for example, a phenoxycarbonyl group, a naphthyloxy carbonyloxy group, etc. are used, "C _{7 -19} aralkyloxy-carbonyloxy group "includes, for example, benzyloxycarbonyloxy group, 1-phenylethyloxycarbonyloxy group, 2-phenylethyloxycarbonyloxy group, benzhydryloxycarbon is such group optionally being used, as the "C _{3 -10} cycloalkyloxy carbonyloxy group", for example, it includes cyclopropyl oxy carbonyloxy group, cyclohexyloxy group optionally Viterbo Brassica is used.

As the "ureido group optionally having substituents", for example, as a substituent of C _{1 -4} alkyl group (e.g., methyl, ethyl, etc.), from 1 to 3 selected from the group including more (in particular, 1 or 2) Optionally substituted ureido groups are used, for example, ureido groups, 1-methyl ureido groups, 3-methyl ureido groups, 3,3-dimethyl ureido groups, 1,3-dimethyl ureido groups, 3-phenyl ureido groups and the like Used.

As a "substituent" of an "aliphatic hydrocarbon group optionally having a substituent", a heterocyclic group, a heterocyclicoxy group, a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group or a heterocyclic oxycarbonyl group When used, a heterocyclic group refers to a group formed by removing one hydrogen atom bonded to a heterocycle, for example, 1 to several hetero atoms such as nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc. 5, 8-membered cyclic (preferably 5-6 membered cyclic) groups containing 1, preferably 1-4, or condensed cyclic groups thereof. Examples of such heterocyclic groups include pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group and tie Neyl group, oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4- Oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxynyl group, dioxolyl group, quinolyl group, pyrido [2 , 3-d] pyrimidyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d ] Pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group, dioxanyl group and the like are used.

These heterocyclic groups, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), hydroxy, oxo, C _{1 -4} alkoxy of 1 to selected from the like (e. G., Methoxy, ethoxy, etc.) It may be substituted at a position substitutable by three substituents.

As the "C _{6 -10} aryl group" of the "C _{6 -10} aryl group optionally having substituents", for example, a phenyl group, a naphthyl group and the like are used. C _{6 -10} aryl groups, the "aliphatic hydrocarbon group optionally having substituents" of the "substituent" (except optionally substituted C _{6 -10} aryl group) may be substituted at possible positions substituted with a substituent selected from the those listed as have. Such a substituent may be a C _{6 -10} are substituted at substitutable positions of the aryl group, the substituent is not limited to one, the same or different, and a plurality (2 to 4).

In addition, in the "aliphatic hydrocarbon group optionally having a substituent", the substituent may form an optionally substituted fused ring group together with the aliphatic hydrocarbon group, and as the condensed ring group, an indanyl group, 1,2,3,4-tetrahydronaphthyl group Etc. are used. Such a condensed ring group may be substituted at a position which may be substituted with a substituent selected from the "substituent" of the "aliphatic hydrocarbon group optionally having a substituent". Such substituents are substituted at substitutable positions of the fused ring group, and the substituents are not limited to one, the same or different, and may be a plurality (2 to 4).

As R, R ^a , R ¹ , R ^1a , R ^1b , R ^1c , for example, a lower alkyl group having 1 to 6 carbon atoms optionally having a substituent (for example, methyl group, ethyl group, n-propyl group, isopropyl group) , n-butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group and the like) are preferably used, and in particular, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, iso Butyl group etc. are used preferably. In particular, a methyl group, an ethyl group, n-propyl group, etc. are preferable, and an ethyl group etc. are especially preferable.

As R ² and R ^2a , for example, a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert- Butoxycarbonylmethyl group, hydrokishiethyl group and the like) are preferably used, and hydrogen atom, methyl group and the like are preferably used, and hydrogen atom and the like are particularly preferably used.

As R ⁰ , R ^0a , for example, a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert- Butoxycarbonylmethyl group, hydroxyethyl group, etc.) are used preferably, and a hydrogen atom, a methyl group, etc. are used preferably.

Examples of the "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having a substituent" represented by R and R ^a include an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, a phenyl group, naphthyl group, biphenyl group, anthryl group, and indenyl group). Etc.), and an aryl group having 6 to 10 carbon atoms (for example, a phenyl group and a naphthyl group) and the like are preferable, and a phenyl group and the like are particularly preferable.

As the "substituents" of "aromatic hydrocarbon group optionally having substituents" represented by R and R ^a, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), lower (C _{1 -4)} alkyl (Eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _{1 -4} ) alkoxy-carbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (e.g., acetylamino group Alkanoylamino groups having 1 to 4 carbon atoms such as propionylamino group and butyryl amino group, cycloalkyl groups having 3 to 6 carbon atoms (e.g., cyclopropyl group, cyclopentyl group, etc.), and aryl groups having 6 to 10 carbon atoms ( For example, phenyl group, naphthyl group, indenyl And the like), a halogeno-lower (C _{1 -4)} alkyl group (e.g., a methyl group, a trifluoromethyl trifluoromethyl group and the like), a halogeno-lower (C _{1 -4)} alkoxy group (e.g., trifluoromethyl Romero Talk group, Messenger when the 1,1,2,2-tetrafluoroethane, 2,2,3,3,3-pentafluoropropane as a propoxy group, etc.), lower (C _{1 -4)} alkyl come tea (e.g. for example, import-methylthiophene, ethyl come tea, propionyl thio group, etc.), lower (C _{1 -4)} alkylsulfonyl group (e.g., a methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.), lower (C _{1 -4} ) alkanoyl groups (eg, formyl groups, acetyl groups, propionyl groups, etc.), 5-membered aromatic heterocyclic groups (eg, 1,2,3-triazolyl groups, 1,2 , 4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isooxazolyl group, thiadiazolyl group, thienyl group, furyl group, etc.), carbamoyl group, lower (C _{1 -4} ) alkyl-carbamoyl groups (eg, methylcar Carbamoyl group and dimethyl carbamoyl group, propionyl carbamoyl group, etc.), lower (C _{1 -4)} alkoxy-carbonyl-lower (C _1-4) alkyl-carbamoyl group (e.g., butoxycarbonyl methyl a carbamoyl group, an ethoxycarbonyl methyl carbamoyl group and the like), 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl group (for example, 1,3-diacetyl-methyl-guanidino, 1, 3-bis -tert- butoxy carbonyloxy nilgu no dino-methyl, etc.) and the like are used, and preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), lower (C _{1 -4} ) An alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.) is used, and more preferably a fluorine atom, a chlorine atom and a methyl group are used.

Such substituents are substituted at substitutable positions of the aromatic hydrocarbon group, the number of substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

The "heterocyclic group" of the "heterocyclic group optionally having a substituent" represented by R and R ^a includes, for example, one to several heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom and a sulfur atom. , Preferably 5 to 8-membered ring (particularly 5 to 6-membered ring) groups having 1 to 4, or condensed ring groups thereof. Examples of such heterocyclic groups include pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group and tie Neyl group, oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4- Oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxynyl group, dioxolyl group, quinolyl group, pyrido [2 , 3-d] pyrimidyl group, 1,5-, 1,6, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] Pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group, dioxanyl group, etc. are used.

These heterocyclic groups, C _{1 -4} alkyl and 1 is selected from the (e. G., Methyl, ethyl, etc.), hydroxy, oxo, C _{1 -4} alkoxy (e.g., methoxy, ethoxy), etc. It may be substituted at a position which may be substituted by three substituents.

Examples of the "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having a substituent" represented by Ar and Ar ^a include an aromatic hydrocarbon group having 6 to 14 carbon atoms (for example, a phenyl group, naphthyl group, biphenyl group, anthryl group, and indenyl group). Etc.) are preferable, and, for example, an aryl group (for example, a phenyl group, a naphthyl group, etc.) having 6 to 10 carbon atoms is particularly preferable, and a phenyl group is particularly preferable.

As the "substituents" of "aromatic hydrocarbon group optionally having substituents" represented by Ar, Ar ^a, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), lower (C _{1 -4)} alkyl (e. g., methyl, ethyl, propyl, butyl, etc.), lower (C _{1 -4)} alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _{1 -4} ) alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (e.g., acetylamino group, C1-C4 alkanoylamino groups, such as propionylamino group and butyrylamino group, C3-C6 cycloalkyl group (for example, cyclopropyl group, cyclopentyl group, etc.), C6-C10 aryl group (for example, For example, phenyl group, naphthyl group, indenyl And the like), a halogeno-lower (C _{1 -4)} alkyl group (e.g., a methyl group, a trifluoromethyl trifluoromethyl group and the like), a halogeno-lower (C _1-4) alkoxy group (e.g., trifluoromethyl Romero Talk group, Messenger when the 1,1,2,2-tetrafluoroethane, 2,2,3,3,3-pentafluoropropane as a propoxy group, etc.), lower (C _{1 -4)} alkyl come tea (e.g. for example, import-methylthiophene, ethyl come tea, propionyl thio group, etc.), lower (C _{1 -4)} alkylsulfonyl group (e.g., a methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.), lower (C _{1 -4} ) alkanoyl groups (eg, formyl groups, acetyl groups, propionyl groups, etc.), 5-membered aromatic heterocyclic groups (eg, 1,2,3-triazolyl groups, 1,2 , 4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isooxazolyl group, thiadiazolyl group, thienyl group, furyl group, etc.), carbamoyl group, lower (C _{1 -4)} alkyl-carbamoyl group (e.g., methylcarbamoyl Group, a dimethyl carbamoyl group, propionyl carbamoyl group, etc.), lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-contains a carbamoyl group (e.g., butoxycarbonylmethylcarbamoyl carbamoyl group, ethoxycarbonyl methyl carbamoyl group and the like), 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl group (e.g., 1,3-diacetyl-methyl-guanidino, 1,3- bis -tert- butoxy carbonyloxy nilgu no dino-methyl, etc.) and the like are used, and preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), lower (C _{1 -4)} alkyl (For example, methyl group, ethyl group, propyl group, butyl group, etc.), etc. are used, More preferably, a fluorine atom, a chlorine atom, and a methyl group are used.

Such substituents are substituted at substitutable positions of the aromatic hydrocarbon group, the number of substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. When two or more substituents are present, these substituents may be the same or different.

Specifically, as Ar or Ar ^a, for example, a phenyl group, halogeno phenyl group, lower (C _1-4) alkyl group, a lower (C _{1 -4)} alkoxy group, a lower (C _{1 -4)} alkoxycarbonyl group, a carboxyl group, a nitro group, a cyano group, a halogeno-lower (C _{1 -4)} alkyl group, a halogeno-lower (C _{1 -4)} alkoxy group, a lower (C _{1 -4)} alkanoyl group, substituted by a 5-membered aromatic heterocyclic group, a lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-carbamoyl group, a 1,3-dia silgu no dino-lower (C _1-4) alkyl group, a halogen and lower (C _1-4) a phenyl group substituted with alkyl, halogen or lower (C _1-4) a phenyl group substituted with alkoxycarbonyl, halogen and cyano-substituted phenyl group, a halogen, and 5 -membered aromatic heterocycle-substituted phenyl group, a halogen and lower (C _{1 -4)} alkoxy-carbonyl-phenyl substituted by carbamoyl-lower (C _{1 -4)} alkyl And the like are used. As Ar or Ar ^a, a halo is halogeno group, a lower (C _{1 -4)} alkyl group, a halogen and lower (C _{1 -4)} a phenyl group substituted with an alkoxy-carbonyl and the like are preferably used.

As Ar or Ar ^a , a group represented by the following formula:

[Wherein, R ⁴ and R ⁵ are the same or different, each represents a halogen atom or a lower alkyl group, n represents an integer of 0 to 2], and R ⁴ and R ⁵ are particularly preferred. It is further more preferable that at least one of them is a halogen atom.

As a halogen atom represented by R <^4> and R <^5> , a fluorine atom or a chlorine atom is preferable.

As the halogenophenyl group, for example, 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3, 5-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2- Chloro-4-fluorophenyl group, 4-bromo-2-fluorophenyl group, 2,3,4-trifluorophenyl group, 2,4,5-trifluorophenyl group, 2,4,6-trifluoro Phenyl group etc. are used.

Lower (C _{1 -4)} alkyl group As, it is preferably used, such as 2-ethyl-phenyl, 2,6-diisopropylphenyl group, examples of the lower (C _{1 -4)} alkoxy group, for example, a 4-methoxy Phenyl and the like are preferably used.

Lower (C _{1 -4)} alkoxy-carbonyl as a phenyl group, 2-ethoxycarbonyl phenyl, 2-methoxycarbonyl phenyl, 4-methoxycarbonyl phenyl group and the like are preferably used, a halogeno-lower (C _1-4) as the alkyl group, for example, a 2-methylphenyl group, and a tree or the like is used preferably fluoro, halogenoalkyl - as the lower (C _1-4) alkoxy group, for example, a 2-trifluoromethoxy A phenyl group, 4- (2,2,3,3,3-pentafluoropropoxy) phenyl group, etc. are used preferably.

As the lower (C _{1 -4)} alkanoyl group, for example, 2-acetyl phenyl group and the like are preferably used, examples of the phenyl group substituted by a 5-membered aromatic heterocyclic group, for example, 4- (2H-1 , 2,3-triazol-2-yl) phenyl group, 4- (2H-tetrazol-2-yl) phenyl group, 4- (1H-tetrazol-1-yl) phenyl group, 4- (1H-1,2 , 3-triazol-yl) are preferably used, such as a phenyl group, a lower (C _1-4) alkoxy-carbonyl-lower (C _{1 -4)} alkyl-as the carbamoyl group, for example, 4- ( N- ethoxycarbonylmethyl-carbamoyl) is preferably used as the group and the like, 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl group, for example, 4- (1,3-bis -tert-butoxycarbonylguanidinomethyl) phenyl group etc. are used preferably.

As the phenyl group substituted by halogen and lower (C _{1 -4)} alkyl, for example, such as 2-fluoro-4-methylphenyl, 2-chloro-4-methylphenyl, 2-methylphenyl 4-fluorophenyl is preferably used, halogen or lower (C _{1 -4)} as a phenyl group substituted with alkoxycarbonyl, for example, 2-chloro-4-methoxycarbonyl-phenyl group and the like are preferably used, halogen and cyano-substituted As the phenyl group, 2-chloro-4-cyanophenyl group or the like is preferably used. As the phenyl group substituted with halogen and 5-membered aromatic heterocyclic, for example, 2-fluoro-4- (1H-1 , 2,4-triazol-as the phenyl group substituted by carbamoyl,-yl) phenyl group and the like are preferably used, halogen or lower (C _1-4) alkoxycarbonyl-lower (C _{1 -4)} - alkyl For example, 2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl group, 2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phene Is such group is preferably used.

More specifically, as Ar or Ar ^a , a phenyl group, ^a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogens (eg, 2,3-difluorophenyl group, 2,3-dichloro Phenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 2-fluorophenyl group, 2 -Chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,3, 4-trifluoromethyl phenyl group, a phenyl group, 2,4,5-trifluoroacetate and the like), halogen and lower (C _{1 -4)} a phenyl group substituted with alkyl (e. g., 2-chloro-4-methylphenyl group, 4 Fluoro-2-methylphenyl group, etc.) are preferable. Among them, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogen atoms (for example, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2 , 6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,5-trifluorophenyl group, etc.), halogen and lower (C _Phenyl groups substituted with _1-4 ) alkyl (for example, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) etc. are preferable. In particular, 2, 4- difluoro phenyl group, 2-chlorophenyl group, 2-chloro-4- fluorophenyl group, 2-chloro-4- methylphenyl group, etc. are preferable, and 2, 4- difluoro phenyl group, 2- Chloro-4-fluorophenyl group etc. are preferable.

In the present specification, ring A ¹ is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) the formula -OR ¹ wherein R ¹ is the same as mentioned above And a cycloalkene optionally substituted with 1 to 4 substituent (s) selected from the group consisting of halogen atoms, (1) an aliphatic hydrocarbon group optionally having a substituent, (2) Preference is given to cycloalkenes which may be substituted with 1 to 4 substituent (s) selected from the group consisting of aromatic hydrocarbon groups optionally having substituents, and (4) halogen atoms.

In the present specification, ring A ² is (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) the formula -OR ¹ wherein R ¹ is the same as mentioned above And a cycloalkene substituted with 1 to 4 substituents selected from the group consisting of (4) halogen atoms, and (1) an aliphatic hydrocarbon group optionally having a substituent, and (2) optionally having a substituent. Preference is given to cycloalkenes substituted with an aromatic hydrocarbon group and (4) 1 to 4 substituent (s) selected from the group consisting of halogen atoms.

The substituents may be substituted on the substitutable carbon atoms of the ring A ¹ or ring A ^2, when the ring A ¹ or ring A ² is substituted by multiple substituents, the substituents may be the same or different. One carbon atom may be substituted by two substituents and different carbon atoms may be substituted by two or more substituents.

Moreover, even if two substituents are substituted by the same carbon atom L, several substituents can substitute on another carbon atom well.

As the "aliphatic hydrocarbon group optionally having a substituent" which is a substituent of the ring A ¹ and the ring A ² , for example, the "substituent represented by the above-mentioned R, R ^a , R ¹ , R ^1a , R ^1b , R ^1c is optionally And the same substituents as the "aliphatic hydrocarbon group having" can be used.

As the "aromatic hydrocarbon group optionally having a substituent" as the substituent of the ring A ¹ and the ring A ² , for example, the same substituent as the "aromatic hydrocarbon group optionally having a substituent" represented by Ar or Ar ^a described above can be used. .

As the substituents of ring A ¹ and ring A ^2, 1 or 2 C _{1 -6} alkyl group (e.g., methyl group, tert- butyl group of C _{1 -4} alkyl group), a phenyl group, a halogen atom (e.g., fluorine , Chlorine, bromine, iodine and the like) are preferably used.

A group represented by the following formula:

[Where n represents the same meaning as defined above] is a group represented by the following formula:

[Where n represents the same meaning as defined above] or a group represented by the following formula:

[Where n represents the same meaning as defined above], and a group represented by the following formula:

[Where n represents the same meaning as defined above] is more preferable.

A group represented by the following formula:

[Where n represents the same meaning as defined above] is a group represented by the following formula:

[Where n represents the same meaning as defined above] or a group represented by the following formula:

[Where n represents the same meaning as defined above], and a group represented by the following formula:

[Where n represents the same meaning as defined above] is more preferable.

The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the formula:

More preferred are those represented by the formula:

.

.

As an integer of 1-4 represented by n, 1-3 are preferable and 2 is more preferable.

As a compound represented by general formula (Iaa), the compound represented by general formula (Ibb) is preferable, and as a compound represented by general formula (Ia), the compound represented by general formula (Ib) is preferable.

As a compound represented by general formula (Ibb), the compound represented by general formula (Inn) is preferable, and as a compound represented by general formula (Ib), the compound represented by general formula (In) is preferable.

Compounds represented by formulas (Ibb) and (Ib), wherein R ¹ is a lower alkyl group optionally having substituents, R ² is a hydrogen atom or a lower alkyl group, Ar is a phenyl group optionally having substituents, n is 1, 2 or 3 A phosphorus compound is preferable, a compound in which R ¹ is a lower alkyl group optionally having a substituent, R ² is a hydrogen atom, Ar is a phenyl group substituted with a halogen atom, and n is 2 is more preferable.

As a compound represented by general formula (Icc) and (Ic), Ar is a phenyl group which optionally has a substituent, and the compound whose n is 2 is preferable.

As the leaving group represented by X ¹ , for example, a halogen atom (for example, chlorine, bromine, iodine, etc.) is preferable, and a chlorine atom is more preferable.

Stereoisomers in the compounds represented by formulas (I), (Iaa), (Ibb), (Icc), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) When present, either of the stereoisomers and mixtures of those stereoisomers are included in the present invention.

Moreover, when the compound represented by general formula (Iaa) is a compound represented by general formula (Icc) or (Inn), when the compound represented by general formula (Ia) is a compound represented by general formula (Ic) or (In), general formula (Ie) When the compound represented by formula (Ik) or (Ip) is a compound represented by formula (Id), when the compound represented by formula (Id) is a compound represented by formula (Ir), and the compound represented by formula (Ig) is represented by formula (lt) In the case of the compounds represented, each compound may exist as optical isomers for asymmetric carbon atoms in the cycloalkenes or cyclohexene rings, and any of the above optical isomers and mixtures of these optical isomers are included in the present invention.

As a compound represented by general formula (I) or (Ia), the compound etc. which are obtained specifically from Reference Example B mentioned later are used, Among them, <1> d-ethyl 6- [N- (2,4- Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1- Carboxylate), <2> ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chlorophenyl) sulfamoyl] Cyclohex-1-ene-1-carboxylate), <3> ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate) or <4> d-ethyl 6- [N- (2-chloro-4-fluorophenyl Sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-car Carboxylate), and Shall preferably a salt thereof.

Compounds (I), (Iaa), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ibb) and (Icc) used in the compositions of the present invention ), Hereinafter simply referred to as a compound of the present invention, can be converted into, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. Can be. Salts with an inorganic base include, for example, alkali metal salts such as sodium salts and potassium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; Aluminum salts, ammonium salts, and the like, and salts with organic bases are, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N ' It may be a salt with dibenzylethylenediamine. Salts with inorganic acids can be, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, salts with organic acids can be, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, Salts with maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and the like. Salts with basic amino acids can be, for example, salts with arginine, lysine or ornithine, and salts with acidic amino acids can be, for example, salts with aspartic acid or glutamic acid.

The compounds of the present invention can be prepared, for example, by the preparation methods described in WO99 / 46242.

(B) chemical formula ( II About the compound of

In the present specification, R ^{1 '} represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a group represented by the formula -OR ^1a' , or a group represented by the following formula :

Especially, group represented by general formula -OR < ^{1a '} is preferable.

As an "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group optionally having substituent" represented by R1 ^' , an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group, etc. are preferable, for example.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group and the like are preferred, and in particular, for example, lower alkyl group having 1 to 6 carbon atoms (for example, Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like).

As a cycloalkyl group, a C3-C10 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc.) etc. are preferable, for example, In particular, a C3-C6 cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.) etc. are preferable, for example.

As the cycloalkylalkyl group, for example, a cycloalkylalkyl group having 4 to 12 carbon atoms (for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) is preferable, and for example, for example, Preferred are cycloalkylalkyl groups having 4 to 8 carbon atoms (especially 4 to 7) (for example, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.).

As the alkenyl group, for example, a lower alkenyl group having 3 to 6 carbon atoms (for example, propenyl group, butenyl group, pentenyl group, etc.) is preferable, and for example, lower alkenyl group having 3 or 4 carbon atoms is preferable. (For example, propenyl group, butenyl group, etc.) etc. are preferable.

As the alkynyl group, for example, a lower alkynyl group having 3 to 6 carbon atoms (for example, propynyl group, butynyl group, pentynyl group, etc.) is preferable, and for example, lower alkynyl group having 3 or 4 carbon atoms ( For example, propynyl group, butynyl group, etc.) are preferable.

Examples of the "substituent" of the "aliphatic hydrocarbon group having optionally a substituent", for example, a heterocyclic group, an oxo group, a hydroxy group, C _{1 -6} alkoxy, C _{3 -10} (in particular, C _{3 -6)} cycloalkyl alkyloxy, C _{6 -10} aryloxy group, C _{7 -19} (in particular, C _{7 -12)} aralkyl oxy group, a heterocyclic oxy group, C _{1 -6} alkylthio group (which is a sulfur atom may be oxidized) , C _{3 -10} (in particular, C _{3 -6)} cycloalkyl alkylthio (which is a sulfur atom may be oxidized), C _{6 -10} arylthio group (the sulfur atom may be oxidized), C _{7 -19} (in particular, C _{7 - 12)} aralkyl come tea (which is a sulfur atom may be oxidized), a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a nitro group, a halogen atom, a cyano group, a carboxyl group, C _{1 -10} (particularly, C _{1 -6)} alkoxy-carbonyl group, C _{3 -6} cycloalkyloxy-carbonyl group, C _6-10 aryloxy-carbonyl group, C _{7 -19} (in particular, C _{7 -12)} aralkyloxy-carbonyl group, heterocyclic Cicle Rick oxycarbonyl group, C _{6 -10} aryl-carbonyl group, C _{1 -6} alkanoyl, C _{3 -5} alkenyl noilgi, C _{6 -10} aryl-carbonyloxy group, C _{2 -6} alkanoyloxy group, C _{3 - 5} Al Keno acryloyloxy group, optionally having substituents carbamoyl group, an optionally thiocarbamoyl group, carbamoyloxy group optionally having a substituent having a substituent, C _{1 -6} alkanoylamino group, C _{6 -10} aryl-carbonyl group, C _{1 -10} (particularly, C _1-6) alkoxy-carboxamide group, C _{6 -10} aryloxy-carboxamide group, C _{7 -19} (in particular, C _{7 -12)} aralkyloxy-carboxamide group, C _{1 -10} (in particular, C _{1 -6)} alkoxy-carbonyloxy group, C _{6 -10} aryloxy-carbonyloxy group, C _{7 -19} (in particular, C _{7 -12)} aralkyloxy-carboxamide carbonyloxy group, C _{3 -10} (particularly, C _3-6) cycloalkyloxy-carbonyloxy group, etc., a ureido group optionally having substituents, C _{6 -10} aryl group optionally having a substituent group are used.

These substituents are substituted at the substitutable position of the "aliphatic hydrocarbon group", and the substituents are not limited to one, the same or different, and may be several (2 to 4).

"C _{1 -6} alkoxy group" as, for example, methoxy, ethoxy, n- propoxy, iso-propoxy, n- butoxy group, tert- butoxy group, n- pen tilok group, a n- hexyl as this is being used, "C _{3 -10} cycloalkyloxy groups" such -1,3 time, for example, as the cyclopropyl-oxy group, cyclohexyloxy group, etc. are used, "C _{6 -10} aryloxy group", for example, phenoxy group, naphthyloxy group, etc. are used, "C _{7 -19} aralkyl-oxy group" as, for example, benzyloxy group, 1-phenylethyl oxy group, 2-phenylethyl oxy group, benzhydryl oxy group, 1-naphthyl-methyl-oxy group, etc. are used, as the "C _{1 -6} (the sulfur atom may be oxidized) alkylthio", for example, methyl thio group, ethyl thio group, n- propyl thio, n- Import butyl tea, methyl sulfinyl group, is used, such as methyl sulfonyl group, "C _{3 -10} (the sulfur atom may be oxidized) cycloalkyl alkylthio" come, for example, cyclopropyl T as, Cyclohexyl silti come, cyclopentyl sulfinyl group, sulfonyl group, cyclohexyl, etc. are used, "C _{6 -10} arylthio group (sulfur atom that may be oxidized)" as, for example, phenylthio, naphthyl tilti come, phenyl a sulfinyl group, a phenyl sulfonyl group, etc. are used, "C _{7 -19} aralkyl come tea (which is a sulfur atom may be oxidized)" as, for example, benzyl thio, thio-phenylethyl, benzhydryl thio, benzyl a sulfinyl group, benzyl-sulfonyl group, etc. are used, "halogen atom" as, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom is used and the like, - as the "C _{1 -10} alkoxycarbonyl groups", for example, methoxy group, ethoxy group, n- propoxy group, isopropoxy group, n- butoxy group, isobutoxy group, a tert- butoxycarbonyl group, etc. are used, as the "C _{3 -6} cycloalkyloxy group", E.g, Cyclopropyl-oxy group, a cyclopentyloxy group, a cyclohexyl oxy group, oxycarbonyl group Nord carbonyl, etc. are used, "C _{6 -10} aryloxy-carbonyl group" as, for example, a phenoxy group, a naphthyloxy group, etc. are used , examples of - "group C _{6 -10} aryl" Yes "C _{7 -19} aralkyl-oxycarbonyl group" as, for example, a benzyloxycarbonyl group, benzhydryl oxy group, a 2-phenethyl oxycarbonyl group and the like are used, and for example, a benzoyl group, naphthoyl group, a phenylacetyl group, etc. are used, "C _{1 -6} alkanoyl" as, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, Sangapi It is used and the like group, as the "C _{3 -5} alkenyl noilgi", for example, acryloyl group, a croissant noilgi agent, etc. are used, "C _{6 -10} aryl-carbonyloxy group" as, for example, benzoyloxy Envy, me Neoplasm? Acryloyloxy group, a phenyl-acetoxy group, etc. are used, as the "C _{2 -6} Kano yloxy time al", for example, acetoxy, propionyloxy oxy group, butynyl group rilok, ballet rilok group, acryloyloxy group, such as blood kicking is used, as the "C _{3 -5} al Keno acryloyloxy group", for example, such as acryloyloxy group of acrylic, chroman teuno acryloyloxy group are used.

As the "carbamoyl group optionally having substituents", for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), phenyl, C _{1 -7} acyl (e.g., acetyl, propionyl, benzoyl, etc. ), C _{1 -4} alkoxy-phenyl (e.g., methoxyphenyl, etc.) one or two substituents, a carbamoyl group or cyclic which may be substituted with a group selected from amino, etc., such as are used, specifically, For example, carbamoyl group, N-methylcarbamoyl group, N-ethyl carbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-phenylcarbamoyl group, N -Acetylcarbamoyl group, N-benzoylcarbamoyl group, N- (p-methoxyphenyl) carbamoyl group, 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, 1-piperazinylcarbonyl group, morpholinocarbonyl group, etc. This is used. "Thiocarboxylic optionally having substituents carbamoyl group" as, for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from phenyl, etc. A diary is used, and a thiocarbamoyl group, N-methylthiocarbamoyl group, N-phenyl thiocarbamoyl group, etc. are used specifically ,. As the "carbamoyloxy group optionally having substituents", for example, C _{1 -4} alkyl (e.g., methyl, ethyl, etc.), carbamoyl which may be substituted with 1 or 2 substituents selected from phenyl, etc. together An oxy group is used, and specifically, a carbamoyloxy group, N-methyl carbamoyloxy group, N, N- dimethylcarbamoyloxy group, N-ethylcarbamoyloxy group, N-phenylcarbamoyl jade is mentioned, for example. The timing is used.

As the "C _{1 -6} alkanoylamino group", for example, acetoamide group, a propionamide group, butyryl amide group, an amide group valerolactone, pivaloyl amide group, etc. are used, "C _{6 -10} aryl-carbonyl amino group "as, for example, a benzamide group, a naphthoyl amide group, an imide group such as phthalimide is used," C _{1 -10} alkoxy-as-carboxamide group ", for example, a methoxy-carboxamide (CH ₃ OCONH-) group, an ethoxy-carboxamide group, a tert- butoxy-carboxamide group, etc. are used, the "C _{6 -10} aryloxy-carboxamide group" as, for example, phenoxy-carboxamide ( C ₆ H ₅ OCONH-) group and the like are used, and as the "C _{7 -19} aralkyloxy-carboxamide group", for example, benzyloxycarboxamide (C ₆ H ₅ CH ₂ OCONH-) group, benz Hi drill aryloxy-carboxamide group, etc. are used, "C _{1 -10} alkoxy-carbonyloxy group" as, for example, a methoxy carbonyloxy group, ethoxy Carbonyloxy group, n-propoxycarbonyloxy group, isopropoxycarbonyloxy group, n-butoxycarbonyloxy group, tert-butoxycarbonyloxy group, n-pentyloxycarbonyloxy group, n -hexyloxy group optionally Brassica Viterbo and the like are used, "C _{6 -10} aryloxy-carbonyloxy group" as, for example, a phenoxycarbonyl group, a naphthyloxy carbonyloxy group, etc. are used, "C _{7 -19} aralkyloxy-carbonyloxy group "includes, for example, benzyloxycarbonyloxy group, 1-phenylethyloxycarbonyloxy group, 2-phenylethyloxycarbonyloxy group, benzhydryloxycarbon is such group optionally being used, as the "C _{3 -10} cycloalkyloxy carbonyloxy group", for example, it includes cyclopropyl oxy carbonyloxy group, cyclohexyloxy group optionally Viterbo Brassica is used.

As the "ureido group optionally having substituents", for example, as a substituent of C _{1 -4} alkyl group (e.g., methyl, ethyl, etc.), from 1 to 3 selected from the group including more (in particular, 1 or 2) An optionally substituted ureido group is used, for example, a ureido group, 1-methyl ureido group, 3-methyl ureido group, 3, 3- dimethyl ureido group, 1, 3- dimethyl ureido group, 3-phenyl ureido group, etc. Used.

As a "substituent" of an "optionally substituted aliphatic hydrocarbon group", a heterocyclic group, heterocyclicoxy group, heterocyclic thio group, heterocyclic sulfinyl group, heterocyclic sulfonyl group or heterocyclic oxycarbonyl group When used, heterocyclic group refers to a group formed by removing one hydrogen atom bonded to a heterocycle, for example, a hetero atom such as a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom, or the like. 5 to 8-membered ring (particularly 5 to 6-membered ring) groups containing from several to several, preferably one to four, or condensed cyclic groups thereof. As the heterocyclic group, for example, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group , Oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxa Diazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3, 4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, pyranyl, thiopyranyl, dioxynyl, dioxolyl, quinolyl, pyrido [2, 3-d] pyrimidyl group, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthythyridyl group, thieno [2,3- d] pyridyl group, benzpyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group, dioxanyl group, etc. are used.

These heterocyclic groups, C _{1 -4} alkyl and 1 is selected from the (e. G., Methyl, ethyl, etc.), hydroxy, oxo, C _{1 -4} alkoxy (e.g., methoxy, ethoxy), etc. It may be substituted at possible positions by three substituents.

As the "C _{6 -10} aryl group" of the "optionally C _{6 -10} aryl group having substituents", for example, a phenyl group, a naphthyl group and the like are used. C _{6 -10} aryl group, the above "aliphatic hydrocarbon group optionally having a substituent", "substituent" may be substituted at possible positions substituted with a substituent selected from (C _{6 -10} aryl group, except optionally substituted). These substituents, and optionally substituted at substitutable position of C _{6 -10} aryl group, the substituent is not limited to one, the same or different, and may be more than one (2 to 4).

In addition, in "an aliphatic hydrocarbon group optionally having a substituent", the substituent may form an optionally substituted condensed ring group together with the aliphatic hydrocarbon group, and as these condensed ring groups, an indanyl group, 1,2,3,4-tetrahydronaph Til group etc. are used. Such a condensed ring group may be substituted at a position which may be substituted with a substituent selected from the "substituent" of the "optionally substituted aliphatic hydrocarbon group". Such substituents are substituted at substitutable positions of the fused ring group, and the substituents are not limited to one, the same or different, and may be several (2 to 4).

As an "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having substituent" represented by R ^{1 '} , a C6-C14 aromatic hydrocarbon group (for example, a phenyl group, naphthyl group, biphenyl group, anthryl group, indenyl group, etc.) ), And particularly preferably an aryl group having 6 to 10 carbon atoms (for example, a phenyl group, a naphthyl group, etc.), and a phenyl group.

Examples of R ^{1 '} "substituents" of "aromatic hydrocarbon group optionally having substituents" represented by, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), lower (C _{1 -4)} alkyl group ( for example, a methyl group, an ethyl group, a propyl group, a butyl group, etc.), lower (C _{1 -4)} alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _{1 - 4} ) Alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (for example, acetylamino group, propy C1-C4 alkanoylamino groups, such as an onylamino group and a butyrylamino group, a C3-C6 cycloalkyl group (for example, a cyclopropyl group, a cyclopentyl group, etc.), and an C6-C10 aryl group (for example, For example, a phenyl group, a naphthyl group, an indenyl group ), A halogeno-lower (C _{1 -4)} alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), trifluoromethyl, halogeno-lower (C _{1 -4)} alkoxy (e.g., trifluoromethoxy Talk time, Flick time to 1,1,2,2-tetrafluoroethane, and 2,2,3,3,3-penta-fluoro-propoxy), a lower (C _{1 -4)} alkyl come tea (e. g., methyl thio group, ethyl thio group, propionyl thio group, etc.), lower (C _{1 -4)} alkylsulfonyl group (e.g., a methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.), lower (C _{1 -4} ) alkanoyl groups (e.g. formyl group, acetyl group, propionyl group, etc.), 5-membered aromatic heterocyclic groups (e.g. 1,2,3-triazolyl group, 1,2, 4-triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, an oxazolyl group, an iso-oxazolyl group, a thiadiazolyl group, a thienyl group, a furyl group and the like), a carbamoyl group, a lower (C _{1 - 4} ) Alkyl-carbamoyl groups (eg methylcarbamoyl groups , Dimethyl carbamoyl group, propionyl carbamoyl group, etc.), lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-contains a carbamoyl group (e.g., butoxycarbonyl methyl carbamoyl group, ethoxycarbonyl methyl carbamoyl group and the like), 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl group (e.g., 1,3-diacetyl-methyl-guanidino, 1,3- bis -tert- butoxy carbonyloxy nilgu no dino-methyl, etc.) and the like are used, and a halogen atom (e.g., fluorine, chlorine, bromine, iodine atom, etc.), lower (C _{1 -4)} alkyl group (e.g., Methyl group, ethyl group, propyl group, butyl group and the like) are preferably used, and fluorine atom, chlorine atom and methyl group are more preferably used.

These substituents are substituted at substitutable positions of the aromatic hydrocarbon group, the number of substituents is preferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. When two or more substituents are present, those substituents may be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R ^{1 '} is preferably 1 to several heteroatoms such as nitrogen atoms (optionally oxidized), oxygen atoms, sulfur atoms, and the like. 5 to 8-membered ring (particularly 5 to 6-membered ring) group having 1 to 4, or a condensed ring group thereof. Examples of such heterocyclic groups include pyrrolyl group, pyrazolyl group, imidazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group and tie Neyl group, oxazolyl group, isoxazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4- Oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3 , 4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxynyl group, dioxolyl group, quinolyl group, pyrido [2 , 3-d] pyrimidyl group, 1,5-, 1,6, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, thieno [2,3-d] Pyridyl groups, benzpyranyl groups, tetrahydrofuryl groups, tetrahydropyranyl groups, dioxolanyl groups, dioxanyl groups and the like are used. These heterocyclic groups, C _{1 -4} alkyl and 1 is selected from the (e. G., Methyl, ethyl, etc.), hydroxy, oxo, C _{1 -4} alkoxy (e.g., methoxy, ethoxy), etc. It may be substituted at a position substitutable by three substituents.

As "the aliphatic hydrocarbon group which optionally has a substituent" represented by R < ^{1a '} , the same thing as the "aliphatic hydrocarbon group which optionally has a substituent" represented by R1 ^' can be used, for example. As R ^{1a ′} , for example, a lower alkyl group having 1 to 6 carbon atoms optionally having a substituent (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-part) Oxycarbonylmethyl group, hydroxyethyl group and the like), and the like, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and the like are preferably used. In particular, a methyl group, an ethyl group, n-propyl group, etc. are preferable, and an ethyl group is especially preferable.

As "the aliphatic hydrocarbon group optionally having substituent" represented by R < ^{1b '} , R <^1c' , the same thing as the "optionally aliphatic hydrocarbon group which has a substituent" represented by R <^1>' can be used. R ^{1b '} And R ^{1c ′} may be, for example, a lower alkyl group having 1 to 6 carbon atoms optionally having a substituent (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert- Butoxycarbonylmethyl group, hydroxyethyl group and the like) are preferably used, and for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and the like are preferably used. . In particular, for example, methyl group, ethyl group, n-propyl group, and the like are preferable, and ethyl group is particularly preferable.

As R ^{1 '} , for example, a lower alkyl group having 1 to 6 carbon atoms optionally having a substituent (for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-part) Oxycarbonylmethyl group, hydroxyethyl group, etc.) are used preferably, Especially, for example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, etc. are used preferably. In particular, a methyl group, an ethyl group, n-propyl group, etc. are preferable, and an ethyl group is especially preferable.

Examples of the substituent of Y, optionally representing a methylene group having a substituent, a methyl group, an ethyl group, n- propyl group, isopropyl group, n- butyl group, an isobutyl group C _{1 -6} alkyl group, hydroxymethyl group, hydroxyethyl group, such as hydroxy-substituted -C _{1 -6} alkyl group, such as, and methoxycarbonyl group, ethoxycarbonyl group, tert- butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, tert- butoxycarbonyl and the like carbonyl -C _{1 -4} alkyl-carbonyl C _{1 -4} alkoxy, such as ethyl. Especially, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is especially preferable.

Examples optionally represented by Y in the substituent of a nitrogen atom having a substituent, a methyl group, an ethyl group, n- propyl group, isopropyl group, n- butyl group, an isobutyl group C _{1 -6} alkyl group, such as hydroxymethyl group, hydroxyethyl group hydroxy-substituted -C _{1 -6} alkyl group, such as, methoxycarbonyl group, ethoxycarbonyl group, tert- butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, tert- butoxycarbonylamino and the like carbonyl -C _{1 -4} alkyl-carbonyl group such as C _1-4 alkoxy. Especially, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is especially preferable.

As an "aromatic hydrocarbon group" of the "aromatic hydrocarbon group optionally having substituent" represented by Ar ', it is a C6-C14 aromatic hydrocarbon group (for example, a phenyl group, a naphthyl group, a biphenyl group, an anthryl group, an indenyl group, etc.). Etc. are preferable, especially an aryl group having 6 to 10 carbon atoms (for example, a phenyl group and a naphthyl group) and the like are preferable, and a phenyl group and the like are particularly preferable.

As the "substituents" of "aromatic hydrocarbon group optionally having substituents" represented by Ar ', for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), lower (C _{1 -4)} alkyl group (e.g. for example, a methyl group, an ethyl group, a propyl group, a butyl group, etc.), lower (C _{1 -4)} alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower (C _{1 -4} ) Alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (for example, acetylamino group, propionyl) An alkanoylamino group having 1 to 4 carbon atoms such as an amino group and a butyryl amino group, a cycloalkyl group having 3 to 6 carbon atoms (for example, a cyclopropyl group and a cyclobentyl group), and an aryl group having 6 to 10 carbon atoms (for example, , Phenyl group, naphthyl group, indenyl group, etc.), Halogeno-lower (C _{1 -4)} alkyl (e.g., trifluoromethyl, methyl, ethyl, etc. trifluoromethyl), halogeno-lower (C _{1 -4)} alkoxy (e.g., trifluoromethoxy group Flick , Flick time to 1,1,2,2-tetrafluoroethane, 2,2,3,3,3-penta-fluoro-propoxy, etc.), lower (C _{1 -4)} alkyl come tea (e.g., Import-methylthiophene, ethyl come tea, propionyl thio group, etc.), lower (C _{1 -4)} alkylsulfonyl group (e.g., a methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.), lower (C _{1 -4} ) Alkanoyl groups (eg formyl group, acetyl group, propionyl group, etc.), 5-membered aromatic heterocyclic groups (eg 1,2,3-triazolyl group, 1,2,4- triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, an oxazolyl group, an iso-oxazolyl group, a thiadiazolyl group, a thienyl group, a furyl group and the like), a carbamoyl group, a lower (C _{1 -4)} Alkyl-carbamoyl groups (eg, methylcarbamoyl groups, Methyl carbamoyl group, propionyl carbamoyl group, etc.), lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-carbamoyl group (e.g., butoxycarbonyl methyl carbamoyl group , ethoxycarbonyl methyl carbamoyl group and the like), 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl group (for example, 1,3-diacetyl-methyl-guanidino, 1,3-bis - tert- butoxy-carbonyl nilgu no dino-methyl, etc.) and the like are used, and preferably a halogen atom (e.g., fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), lower (C _{1 -4)} alkyl group (e.g. For example, a methyl group, an ethyl group, a propyl group, a butyl group, etc.) etc. are used, More preferably, a fluorine atom, a chlorine atom, and a methyl group are used.

These substituents are substituted at the substitutable position of an aromatic hydrocarbon group, 1-5 are preferable, as for the number of substituents, 1-3 are more preferable, and 1-2 are especially preferable. When two or more substituents are present, these substituents may be the same or different.

Specifically, for example, phenyl group, halogeno phenyl group, lower (C _{1 -4)} alkyl group, a lower (C _{1 -4)} alkoxy group as Ar '- group, a lower (C _{1 -4)} alkoxy-carbonyl group , a carboxylic acid group, a nitro group, a cyano group, a halogeno-lower (C _{1 -4)} alkyl-phenyl group, a halogeno-lower (C _{1 -4)} alkoxy-phenyl group, a lower (C _{1 -4)} alkanoyl - group, a 5-membered aromatic phenyl group substituted by a heterocyclic, lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-carbamoyl group, a 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl-phenyl group, a halogen and lower (C _{1 -4)} phenyl group, a halogen and lower (C _{1 -4)} alkoxy optionally substituted with an alkyl-phenyl group, halogen and cyano-substituted phenyl group substituted with a carbonyl , halogen and 5-membered aromatic heterocycle-substituted phenyl group, a halogen and lower (C _{1 -4)} alkoxy-carbonyl-using a phenyl group substituted with a carbamoyl-lower (C _{1 -4)} alkyl The.

As the halogenophenyl group, for example, 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3, 5-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2- Chloro-4-fluorophenyl group, 4-bromo-2-fluorophenyl group, 2,3,4-trifluorophenyl group, 2,4,5-trifluorophenyl group, 2,4,6-trifluoro Phenyl group etc. are used.

Lower (C _{1 -4)} alkyl-phenyl group as, for example, a 2-ethylphenyl group, 2,6-diisopropylphenyl group and the like are preferably used, a lower (C _{1 -4)} alkoxy-phenyl group as, for 4-methoxyphenyl group etc. are used preferably.

Lower (C _{1 -4)} alkoxy-carbonyl as a phenyl group, 2-ethoxycarbonyl phenyl, 2-methoxycarbonyl phenyl, 4-methoxycarbonyl phenyl group and the like are preferably used, a halogeno-lower (C _1-4) alkyl-phenyl group as, for example, 2-fluoro-phenyl tree group and the like are preferably used, halogeno-lower (C _{1 -4)} alkoxy - as a phenyl group, a 2-trifluoromethoxyphenyl group, 4 -(2,2,3,3,3-pentafluoropropoxy) phenyl group and the like are preferably used.

Lower (C _{1 -4)} alkanoyl-phenyl group as, for example, 2-acetyl group and the like are preferably used, examples of the phenyl group substituted by a 5-membered aromatic heterocyclic group, for example, 4- (2H-1 , 2,3-triazol-2-yl) phenyl group, 4- (2H-tetrazol-2-yl) phenyl group, 4- (1H-tetrazol-1-yl) phenyl group, 4- (1H-1,2 , 3-triazol-1-yl) phenyl group are preferably used, and lower (C _{1 -4)} alkoxy-carbonyl-lower (C _{1 -4)} alkyl-as the carbamoyl group, for example, 4- (the N- ethoxycarbonylmethyl-carbamoyl) group and the like are preferably used, 1,3-dia silgu no dino-lower (C _{1 -4)} alkyl-phenyl group as, for example, 4- (1,3 Bis-tert-butoxycarbonylguanidinomethyl) phenyl group etc. are used preferably.

As the phenyl group substituted by halogen and lower (C _{1 -4)} alkyl, for example, such as 2-fluoro-4-methylphenyl, 2-chloro-4-methylphenyl, 2-methylphenyl 4-fluorophenyl preferably used, and as the phenyl group substituted by halogen and lower (C _{1 -4)} alkoxycarbonyl, for example, 2-chloro-4-methoxy-carbonyl group and the like are preferably used, halogen and cyano-substituted phenyl group As the phenyl group, for example, a 2-chloro-4-cyanophenyl group or the like is preferably used, and as a phenyl group substituted with a halogen and a 5-membered aromatic heterocycle, for example, 2-fluoro-4- (1H-1, 2, 4-triazol-1-yl) phenyl group are preferably used, and halogen and lower (C _{1 -4)} alkoxycarbonyl-lower (C _1-4) alkyl-as a phenyl group substituted with carbamoyl, e For example, 2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl group, 2-chloro-4- (N-ethoxy carbonylmethylcarba Yl) phenyl group and the like are preferably used.

As Ar ', a halogeno group, a lower (C _{1 -4)} alkyl-phenyl group, a halogen and lower (C _{1 -4)} alkoxy-phenyl group is substituted by a carbonyl, etc. are preferably used.

More specifically, as Ar ', a phenyl group, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogen atoms (e.g., 2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2 , 4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4 -Difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group , 3-fluorophenyl group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,3,4-tri a phenyl group, a phenyl group such as 2,4,5), trifluoromethyl, a phenyl group (e.g., substituted by halogen and lower (C _{1 -4)} alkyl, g., 2-chloro-4-methylphenyl, 4-fluoro- 2-methylphenyl group etc.) etc. are preferable. In particular, a phenyl group substituted with 1 to 3 (particularly 1 to 2) halogens (eg, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2, 6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,5-trifluorophenyl group, etc.), halogen and lower (C _{1 -4} ) Phenyl group substituted with alkyl (for example, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) etc. is preferable. In particular, as Ar ', group represented by a following formula is preferable:

,

,

More preferred are those represented by the formula:

.

.

As the halogen atom represented by R ³ in formula (c ') and the substituent of ring B, and the halogen atom represented by R ^3a and R ^3b in formula (c1'), a fluorine atom or a chlorine atom is preferable. Formula (c ') of the examples of the lower alkyl group represented by R ^3, for example, include a C _{1 -4} alkyl group such as methyl, ethyl, propyl. Among the groups represented by the formula (c '), 2,4-difluorophenyl group, 2-chloro-4-fluorophenyl group, 2-methyl-4-chlorophenyl group and the like are preferable, and are represented by the formula (c1'). Among the groups, 2,4-difluorophenyl group, 2-chloro-4-fluorophenyl group and the like are preferable.

X represents a methylene group, a nitrogen atom, a sulfur atom or an oxygen atom, and in particular, a nitrogen atom, a sulfur atom or an oxygen atom is preferable.

Ring A is a group represented by the formula: -CO-R ^{1 '} , wherein R ^1' is as defined above, and a formula: -SO ₂ -Y-Ar ', wherein Y and Ar' are defined above And (1) an aliphatic hydrocarbon group optionally substituted with a substituent, (2) an aromatic hydrocarbon group optionally substituted with (3) a chemical formula: -OR ^{2 '} (Wherein R ^{2 ′} represents a hydrogen atom or an aliphatic hydrocarbon group optionally having a substituent), and (4) optionally further substituted with 1 to 4 substituent (s) selected from the group consisting of halogen atoms. 1 to 4 substituent (s) selected from the group consisting of a 5-8 membered ring and (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, and (4) a halogen atom Preference is given to 5- to 8-membered rings optionally substituted with.

As "the aliphatic hydrocarbon group optionally having substituent" represented by R <^2>' , the same thing as the "optionally aliphatic hydrocarbon group which has a substituent" represented by R <^1>' can be used.

These substituents are substituted at the substitutable position on Ring A. When X forming the ring is a nitrogen atom or a methylene group, the nitrogen atom or the methylene group may also be substituted. When ring A is substituted with several substituents, the substituents may be the same or different. In addition, two substituents may be substituted on the same carbon atom.

"An aliphatic hydrocarbon group having optionally a substituent" substituent of ring A, and as the "optionally an aromatic hydrocarbon group having a substituent" represented by the above-described R ^{1 '} "aliphatic hydrocarbon group having optionally a substituent group" and "optionally aromatic group having a substituent Hydrocarbon groups "are included.

As the substituent of ring A, 1 or 2 C _{1 -6} alkyl group (e.g., methyl group, tert- butyl group of C _{1 -6} alkyl group), a phenyl group, a halogen atom (e.g., fluorine atom, chlorine atom, Bromine atom, iodine atom, etc.) etc. are used preferably.

m represents an integer of 0-2, n 'represents the integer of 1-3, the sum of m and n' is 4 or less, It is preferable that m is 1 and n 'is 1 further.

As a compound represented by general formula (II), the following compound etc. are preferable, for example.

· R ^{1 'has} the formula: -OR ^{1a "(R 1a"} represents a C _{1 -6} alkyl group), a group represented by the following group represented by the formula:

A group represented by the following formula:

X is methylene or an oxygen atom, Y is methylene or -NH-, which Ar 'is a phenyl group having 1 or 2 substituents selected from the group consisting of a halogen atom and a C _{1 -6} alkoxy, optionally a compound (II).

· R ^{1 'has} the formula: -OR ^{1a "(R 1a"} represents a C _{1 -6} alkyl group), a group represented by the following group represented by the formula:

A group represented by the following formula:

X and Y are methylene or X is an oxygen atom, Y is -NH- and Ar 'is a phenyl group optionally having two halogen atoms (e.g., 2-chloro-4-fluorophenyl group, etc.) (II).

(3) ethyl 6- (benzylsulfonyl) -1-cyclohexene-1-carboxylate (compound 86), ethyl 6-[(4-methoxybenzyl) sulfonyl] -1-cyclohexene-1-car Carboxylate (compound 87), ethyl 6-[(2,4-difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 88), ethyl 6-[(2-chloro-4 -Fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 89), ethyl (-)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclo Hexene-1-carboxylate (compound 90), ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -cyclohexene-1-carboxylate (compound 91), ethyl 3 -[(2,4-difluorophenyl) sulfamoyl] -3,6-dihydro--2H-pyran-4-carboxylate (compound 92) or ethyl 3-[(2-chloro-4-fluoro Rophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (Compound 93).

(4) ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 89), ethyl (+)-6-[(2-chloro- 4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 91) or ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3,6-dihydro -2H-pyran-4-carboxylate (compound 93).

Salts of the compounds represented by the formula (II) include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids. The salt with the inorganic base may be, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, aluminum salts, ammonium salts, and the like, and salts with organic bases may be, for example. , Salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Salts with inorganic acids can be, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid, and salts with organic acids can be, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid. , Maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid and the like. Salts with basic amino acids can be, for example, salts with arginine, lysine, ornithine and the like, and salts with acidic amino acids can be, for example, salts with aspartic acid or glutamic acid.

When stereoisomers are present in the compound represented by the formula (II) or salts thereof, any of such stereoisomers and mixtures thereof is included in the present invention.

In addition, when an optical isomer exists in the compound represented by general formula (II), and its salt, any of such optical isomers and mixtures thereof is included in this invention.

The above-mentioned compounds can be prepared according to the preparation method described, for example, in WO01 / 10826.

Prodrugs of the compounds of the present invention or salts thereof are compounds which are converted into compounds of the present invention by reaction with enzymes or gastric acids under physiological conditions in vivo, that is, enzymatically oxidizing, reducing or hydrolysing the compounds of the present invention. It is a compound which forms and a compound which is hydrolyzed by gastric acid and forms the compound of this invention. Prodrugs of the compounds of the invention include compounds in which the amino groups of the compounds of the invention are acylated, alkylated, and phosphorylated (e.g., the amino groups of the compounds of the invention are eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated compounds and the like); Compounds in which the hydroxyl group of the compounds of the invention are acylated, alkylated, phosphorylated and borated (e.g., the hydroxyl groups of the compounds of the invention are acetylated, palmitoylated, propanoylated, pivaloylated, sulfinylated, fumarylated , Alanylated and dimethylaminomethylcarbonylated compounds); Compounds in which the carboxyl groups of the compounds of the present invention are esterified or amidated (eg, carboxyl groups of the compounds of the present invention are ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl Esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonyl ethyl ester And methylated compounds). These compounds can be prepared from the compounds of the present invention according to methods known per se.

Prodrugs of the compounds of the present invention are also described in "IYAKUHIN no KAIHATSU (Development of Pharmaceuticals)" Vol. 7, Design of Molecules, p.163-198, published by HIROKAWA SHOTEN (1990). It may be converted to a compound of the present invention under physiological conditions.

The compounds of the present invention, salts thereof and prodrugs thereof can be prepared according to methods known per se, for example, the production method described in WO99 / 46242 or a method equivalent thereto.

The compounds of the present invention, salts thereof, and prodrugs thereof can be hydrated or non-hydrated.

The compounds of the present invention, their salts and prodrugs thereof can be labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like.

According to the composition of the present invention, a compound which is stable in an acidic region such as a compound of the present invention, a salt thereof and a prodrug thereof having poor water solubility can be effectively used as a component of a composition composed of an emulsifier.

Compounds that are stable in the acidic region, specifically compounds of the present invention, salts and prodrugs thereof, may exist in the liquid or solid state in the oil phase, and the compositions of the present invention may be in the water-in-type (type 0 / W) or S / 0 / W type emulsion composition.

The composition of the present invention can be prepared, for example, using an emulsifier.

In the composition of the present invention, specifically, dispersed phase particles and dispersed phase particles containing an oil component, an emulsifier, and a compound (specifically, a compound of the present invention or a salt thereof and a prodrug thereof) which are stable in an acidic region are dispersed. It consists of water with a buffer. Disperse phase particles are disperse phases in which one of two liquids that do not mix with each other exists as fine particles on the other liquid surface.

As the oil component, any pharmaceutically acceptable fats and oils conventionally used in the manufacture of fat emulsions in the pharmaceutical art can be used. Oils and fats include, for example, vegetable oils, oils obtainable by partial hydrogenation of vegetable oils, oils obtainable by transesterification reactions (simple glycerides or mixed glycerides), and heavy chains. Fatty acid glycerol esters.

The fats and oils include glycerol esters of fatty acids having about 6 to 30 carbon atoms (preferably about 6 to 22 carbon atoms). Examples of the fatty acid include saturated fatty acids such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and behenic acid; Unsaturated fatty acids such as palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, eicosaptanoic acid, docosahexaenoic acid, and the like.

Preferred oil components include, for example, soybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn sprout oil, sunflower oil, foreskin oil, olive oil and the like. Among these vegetable oils, soybean oil and the like are preferably used.

As fats and oils, medium-chain fatty acid triglycerides having about 6 to 14 carbon atoms, preferably about 8 to 12 carbon atoms, can be used. Preferred glycerin esters of medium-chain fatty acids are caprylic // such as "Migriol 810" and "Migriol 812" (both trade names, manufactured by Huls Co., Ltd., available from Mitusba Trading Co., Ltd.). Glyceryl tricaprylate (tricapryline), such as capric acid triglyceride, "Penasate 800" (product name, manufactured by NOF Corporation, Japan).

The composition of the present invention comprises an oil component in a fraction of, for example, about 1 to about 30 weight percent, preferably about 2 to about 25 weight percent, and more preferably about 2.5 to about 22.5 weight percent, relative to the entire composition It contains.

As the emulsifier, any pharmaceutically acceptable emulsifier can be used. Specifically, pharmaceutically acceptable phospholipids and nonionic surfactants are preferred. Emulsifiers may be used alone or as a mixture of two or more thereof.

Phospholipids include, for example, phospholipids (eg, egg yolk lecithin, soybean lecithin, etc.) obtained naturally, hydrogenated products thereof, or phospholipids (eg, phosphatidylcholine, phosphatidylethanolamine) obtained synthetically. , Phosphatidic acid, phosphatidylserine, phosphatidylinositol, or phosphatidylglycerol, and the like). Among these phospholipids, egg yolk lecithin, soybean lecithin, and phosphatidylcholine from egg yolk and soybean are preferred. The most preferred phospholipid is lecithin. Among the synthetic phospholipids, anionic phospholipids are preferable, and specific anionic synthetic phospholipids include dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, and oleoyl palmitoyl. Phosphatidylglycerol, dioctanoylphosphatidic acid, didecanoylphosphatidic acid, dilauroylphosphatidic acid, dimyristoylphosphatidic acid, diparmitoylphosphatidic acid, diheptadecanoylphosphatidic acid, distea Roylphosphatidic acid, dioleoylphosphatidic acid, arachidylstearoyl phosphatidic acid, dipalmitoylphosphatidylserine, dioleoylphosphatidylserine, dimyristoylphosphatidyl inositol, dipalmitoylphosphatidyl inositol, distea Loylphosphatidyl inositol, dioleoylphosphatidyl inositol, dimyristoyl phosphatide Serine, and the like in one phosphatidylcholine distearoyl, preferable examples include di-myristoyl-phosphatidylglycerol.

These anionic synthetic phospholipids can be chemically synthesized using a method known per se or can be obtained by purification.

Nonionic surfactants include polymeric surfactants having a molecular weight of about 800 to 20000, such as polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene alkyl ethers, polyoxyethylene alkyl aryl ethers, hydrogenated castor oil polyoxyethylene Derivatives, polyoxyethylene sorbitan derivatives, polyoxyethylene sorbitol derivatives, polyoxyethylene alkyl ether sulfates and the like.

Phospholipids and nonionic surfactants as emulsifiers may be used alone or as a mixture of two or more thereof. In addition, commercially available phospholipids can be used.

The total amount of emulsifier in the composition of the present invention is usually about 0.1 to about 10% (W / V), preferably about 0.2 to about 7% (W / V), more preferably, relative to the entire composition of the present invention. Is about 0.5 to about 5% (W / V). The anionic synthetic phospholipids are about 0.0001 to about 5% (W / V) for the total composition.

In the compositions of the present invention, the fraction of the emulsifier relative to the oil component is, for example, about 0.1 to about 150% by weight, preferably about 0.5 to about 125% by weight, more preferably about 1 to about 100% by weight. to be. Emulsifiers are usually used in fractions of about 1 to about 15% by weight, in particular about 1 to about 10% by weight, relative to the oil component.

The water used in the present invention is not particularly limited as long as it is acceptable as a medicine, and includes, for example, purified water and water for injection (injectable distilled water). There is no restriction | limiting in particular also when manufacturing products other than a pharmaceutical.

The amount of water used in the present invention with respect to the total composition is usually about 40 to about 99% (W / V), preferably about 55 to about 98.8% (W / V).

The composition of the present invention may be prepared by mixing and emulsifying a dispersed phase component consisting of a compound of the present invention, a salt thereof and a prodrug (main drug), an oil component and an emulsifier, and a buffer may be added to the aqueous phase before emulsification. Or may be added to the emulsion composition after emulsification. If necessary, a stabilizer for improving the stability of the main drug, an isotonic agent for adjusting the osmotic pressure, an emulsifying aid for improving the emulsifying power, an emulsion stabilizer for improving the stability of the emulsifier may be added.

Stabilizers include, for example, antioxidants (eg, ascorbic acid, tocopherol, sorbic acid, retinol, and the like), chelating agents (eg, edetic acid, citric acid, tartaric acid, and the like, and salts thereof). The amount of stabilizer used is usually about 0.001 to about 10% (W / V), preferably about 0.0001 to about 5% (W / V), based on the entire composition of the present invention.

Isotonic agents include, for example, glycerin, sugar alcohols, monosaccharides, disaccharides, amino acids, dextran, albumin and the like. These isotonic agents can be used 1 type or in mixture of 2 or more types.

Examples of the emulsifying aid include fatty acids having about 6 to 30 carbon atoms, salts of these fatty acids, monoglycerides of fatty acids, and the like. Examples of the fatty acid include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitooleic acid oleic acid, linoleic acid, arachidonic acid, eicosaptanic acid, Docosahexaenoic acid and the like. Examples of salts of fatty acids include alkali metal salts such as sodium salts and potassium salts, calcium salts and the like.

Emulsifying stabilizers include, for example, cholesterol, cholesterol esters, tocopherols, albumin, fatty acid amide derivatives, polysaccharides, derivatives of fatty acid esters of polysaccharides, and the like.

The concentration of a stable compound (hereinafter simply referred to as a compound of the present invention, a salt thereof, or a prodrug) in the acidic region of the composition of the present invention varies depending on the pharmacological activity or blood dynamics of the compound, and is usually from about 0.001 to about 5% (W / V), preferably about 0.01 to about 2% (W / V), more preferably about 0.1 to about 1.5% (W / V). In addition, the content of a compound of the present invention, a salt thereof, or a prodrug thereof in the composition of the present invention is about 1 to about 5000 mg, preferably about 10 to about 2000 mg, more preferably about 100 ml of the composition. It can be set from 100 to about 1500 mg. In addition, the content of a compound of the present invention, a salt thereof, or a prodrug thereof may be added in an amount of about 0.001 to about 95% by weight, preferably about 0.01 to about 30% by weight, more preferably about 0.1 to about 3, based on the total volume of the composition. It can be adjusted by weight%.

The fraction (% by weight) of the compounds of the present invention, salts thereof, or prodrugs thereof in terms of the dispersed phase comprising an oil component and an emulsifier is usually from about 0.0047 to about 24%, and preferably from about 0.047 to about 9.4%.

The compositions of the present invention have a pH adjusted from about 3.7 to about 5.5, preferably from about 3.7 to about 5.0, more preferably from about 4.0 to about 5.0.

Examples of the pH adjuster include phosphoric acid, carbonic acid, citric acid, hydrochloric acid, sodium hydroxide and the like, and hydrochloric acid and sodium hydroxide are particularly preferable.

As the buffer, any pharmaceutically acceptable buffer may be used. Buffers consisting of the following components are preferred, and examples of components include acetic acid, glacial acetic acid, lactic acid, citric acid, phosphoric acid, carbonic acid, histidine, glycine, barbital, phthalic acid, adipic acid, ascorbic acid, maleic acid, succinic acid, tartaric acid, glutamic acid , Benzoic acid, aspartic acid and salts thereof (e.g., potassium, sodium, and the like), and specific examples thereof include sodium acetate, sodium lactate, sodium citrate, dihydrogen phosphate disodium, monosodium dihydrogen phosphate, sodium carbonate, hydrogen carbonate Sodium, hydrochloric acid, sodium hydroxide and the like. In addition, each buffer may be used in combination. In particular, one or more buffers selected from acetic acid buffer, glacial acetic acid buffer, lactic acid buffer, citric acid buffer and phosphate buffer are preferably used.

As the buffer, (i) a combination of acetic acid or glacial acetic acid and sodium acetate (acetic acid buffer or glacial acetic acid buffer), (ii) a combination of lactic acid and sodium lactate (lactic acid buffer) and the like are preferably used.

The concentration of the buffer is usually about 100 mM or less, specifically about 0.1 mM to about 100 mM, preferably about 0.2 to about 50 mM, more preferably about 5 mM to about 40 mM.

A pH adjuster is an acid or alkali compound added in order to adjust pH of a solution to pH aimed at.

In general, the compounding amount of the pH adjuster formulated at the time of injection is very small, and in many fatty emulsifiers commercially available in Japan, the compounding amount of sodium hydroxide as the pH adjuster in the fatty emulsifier is about 0.5 mM or less. In adjusting the solution, the pH can be adjusted to the desired pH, but the pH of the solution is likely to change due to the addition of an acid or an alkali, which makes it difficult to maintain the pH.

A buffer is a compound that acts to alleviate changes in pH due to the addition of an acid or an alkali, that is, a buffer. In many cases, it is a weak acid and its salt, or a mixed solution of the weak base and its salt.

The emulsion composition of the present invention is not affected by the generation of free fatty acids by incorporating a buffer, and it is possible to keep the pH of the emulsion composition constant during autoclave sterilization with steam and long term storage.

Since the compounding amount of the buffer used for general injection is for the purpose of buffering action, the amount of the acetic acid buffer in the injection solution commercially available in Japan is about 0.2 mM to about 100 mM, for example.

The composition of the present invention is preferably used, for example, as an injectable composition.

The composition of the present invention can be basically prepared according to a known method or a method corresponding thereto. For emulsification, conventional emulsification techniques can be used. It is preferable to dissolve or disperse the compound of the present invention, a salt thereof or a prodrug thereof in an oil component in advance. That is, by dispersing (1) a dispersed phase containing an oil component and an emulsifier, and (2) a mixture of a compound of the present invention, a salt thereof, or a prodrug thereof in water, a 0 / W type or S / 0 / W type emulsion Obtained composition is obtained. Buffers may be added to the aqueous phase before emulsification, or may be added to the emulsion composition after emulsification. The mixture to be emulsified can be prepared by mixing the aqueous phase with the oil phase, or by mixing the oil phase with the aqueous phase. Moreover, additives such as stabilizers, isotonic agents and the like can be added to the aqueous and oil phases.

Examples of more preferred methods include, for example, liquid mixtures of additives such as the main drug, oil components, emulsifiers, if necessary, isotonic agents, and heterogeneous mixtures with water containing buffers, by homogenizing in an emulsifier to roughly emulsified emulsions. To obtain water-in-type composition by adding water as needed, further homogenizing the resulting approximately emulsified emulsion using an emulsifier, and removing large particles by filtration means such as filters. Included methods are included. The mixture is generally warmed to, for example, about 30 to about 90 ° C., preferably about 40 to about 80 ° C. to dissolve or disperse the main drug. As the emulsifier for emulsifying the heterogeneous mixture of the mixture and water, a conventional apparatus, for example, a homogenizer such as a pressure spray homogenizer, an ultrasonic homogenizer, a homogeneous mixer such as a high speed mixer, or the like can be used. have. In order to remove large particle | grains in an emulsifier, the homogenized emulsion liquid can be provided to filtration means, such as a filter. The pore diameter of the filter to be used is, for example, about 0.8 to about 20 mu m, preferably about 1 to about 10 mu m.

In the composition of the present invention, the average particle size distribution of the dispersed phase in which the compound of the present invention, a salt thereof, or a prodrug thereof is dissolved is, for example, mostly about 0.01 to about 7 μm, and preferably about 0.02 to about 5 μm. to be. In view of the stability of the emulsion and the biodistribution after administration, the average particle size of the dispersed phase particles in which the compound of the present invention, a salt thereof, or a prodrug thereof is dissolved is, for example, about 0.025 to about 0.7 μm, and preferably about 0.05 To about 0.4 μm.

As used herein, the average particle size refers to the average particle size based on the volume distribution, and is the dispersed phase average particle size measured by a laser-diffraction particle size analyzer based on a laser diffraction and scattering method.

Pyrogen can be removed from the compositions of the present invention using self-known methods.

The composition of the present invention is sterilized and sealed after nitrogen gas substitution, if necessary.

In the emulsion composition of the present invention, the pH is adjusted to about 3.7 to about 5.5 by adding a buffer. Therefore, even after sterilization with an autoclave or the like or after long-term storage, the pH of the emulsion composition and the average particle size of the dispersed phase particles hardly change, and the composition is stable. As a result, the emulsion composition of the present invention, and the compound which is the active ingredient of the emulsion composition, or a salt thereof or a prodrug thereof, exhibit excellent stability. Furthermore, even after sterilizing the emulsified composition of the present invention in an autoclave or the like and storing for a long time, there is no visible visible oil droplet. That is, the dispersed phase particles and the water in which the dispersed phase particles are dispersed are not phase separated and are stable.

In addition, since the pH of the emulsified composition of the present invention can be adjusted to about 3.7 to about 5.5 by adding a buffer, a stable emulsion composition can be provided. You can decide. Thus, even when there are other conditions that can be overcome by adjusting the pH in the range of about 3.7 to about 5.5, such as in the case of affecting the stability of the emulsion composition, an emulsion composition that satisfies various conditions by selecting a pH adjustment. Can be obtained.

Moreover, the emulsion composition of the present invention exhibits long term storage stability of 24 months. This is in excess of 18 months, which is the general duration of use of an emulsified formulation.

In addition, in the emulsion composition of the present invention, the concentration of a compound (particularly a compound of the present invention, a salt thereof or a prodrug thereof) stable in the acidic region may be increased. As the optimal formulation design, the oil component and emulsifier are optimally selected, nonionic surfactants (polyoxyethylene compounds (such as polyethylene glycol, polysorbate, etc.), etc.) are added, and the surface of the dispersed phase particles is modified. By adjusting the particle size of the dispersed phase particles, etc., the retention in blood, vascular permeability and mobility to the site of inflammation can be improved. Thus, targeting can be achieved, thereby improving the pharmacokinetics and biodistribution of the compounds of the present invention, their salts or their prodrugs, ie the drug can be administered more effectively with less side effects. Therefore, the emulsion composition of the present invention is particularly useful for treating target diseases by intravenous administration.

When a compound stable in the acidic range is a compound of the present invention, or a salt thereof or a prodrug thereof, the compound, a salt thereof, and a prodrug thereof have low toxicity, a nitric oxide (NO) production-inhibitory effect, and a TNF-a, IL- Because of having an inhibitory effect on the production of inflammatory cytokines such as 1 and IL-6, the compositions of the present invention can be used for sepsis, including severe sepsis, as well as for mammals (eg, cats, cattle, dogs, horses, goats, monkeys, humans). Etc., useful for the prevention / treatment of heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, septic shock, hypogonadism, etc. Examples of diseases include sepsis, endotoxin shock, exotoxin shock, Systemic immune response syndrome (SIRS), target anti-inflammatory response syndrome (CARS), burns, trauma, postoperative complications, heart failure, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer, Stressful gastric ulcer, Crohn's disease, autoimmune disease, tissue dysfunction and rejection after transplantation, ischemic reperfusion disorder, acute coronary microvascular embolism, shock vascular embolism (such as disseminated intravascular coagulation (DIC)), ischemic Brain disorders, atherosclerosis, pernicious anemia, Fanconi's anemia, sickle cell disease, pancreatitis, neprogen syndrome, nephritis, kidney failure, insulin-dependent diabetes, insulin-independent diabetes, hepatic porphyrinosis, alcoholism, Parkinson's Disease, chronic leukemia, acute leukemia, tumors, myeloma, infant and adult respiratory distress syndrome, emphysema, dementia, Alzheimer's disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy Myocardial infarction, myocardial infarction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, pain relief, influenza infection, malaria, human immunodeficiency virus (HIV) Syndrome, radiation disorders, burns, in vitro fertilization efficiency, hypercalcemia, spastic spondylitis, osteopenia, Behcet's disease, osteomalacia, fractures, acute bacterial meningitis, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic Fever, herpes simplex virus infection, varicella-herpes zoster virus infection, human papilloma virus infection, acute viral encephalitis, encephalitis, meningitis, infectious immune dysfunction, asthma, atopic dermatitis, allergic rhinitis, reflux esophagitis, fever, Hypercholesterolemia, hyperglycemia, hyperlipidemia, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, gout, gastric disability, external hemorrhoids, systemic lupus erythema, spinal cord injury, insomnia, schizophrenia, epilepsy, cirrhosis, liver failure , Unstable angina, heart valve disease, dialysis-induced thrombocytopenia, acute ischemic stroke, acute Sexual cerebral thrombosis, cancer metastasis, bladder cancer, breast cancer, cervical cancer, colon cancer, stomach cancer, ovarian cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, Side effects of administration of anticancer or immunomodulatory agents.

In addition, the compositions of the present invention are useful as inhibitors of TLR signals. 'TLR signal' means any Toll-type receptor that delivers a signal that induces a biological defense response by recognizing a mycological component of a microorganism, and the like, for example, the generally known signal transductions of TLR 1 to TLR 10 This includes.

Since the compounds of the present invention, salts thereof and prodrugs thereof have low toxicity, have a TLR signaling inhibitory effect, and regulate the production of inflammatory mediators such as NO and / or cytokines, the compositions of the present invention are prone to organ failure and the like. Useful for the prevention / treatment of diseases causing signal changes. As used herein, an organ refers to each organ of the central nervous system, the circulatory system, the respiratory system, the bone-joint system, the digestive system, or the kidney-urinary tract system.

The compositions of the present invention, as inhibitors of TLR signaling, are useful for the prevention / treatment of the following diseases caused by TLR signal changes:

(1) Central nervous system diseases [(i) Neurodegenerative diseases (e.g., senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, muscular dystrophy axon sclerosis, diabetes ) Neuropathy (e.g., neuropathy), (ii) neurological disorders (e.g., cerebral vascular insufficiency such as cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis), head trauma-spinal cord injury, encephalitis sequelae, or cerebral palsy, ( iii) memory disorders (eg, senile dementia, forgetfulness, etc.), in particular, Alzheimer's disease,

(2) circulatory diseases [(i) ischemic syndromes such as acute myocardial infarction, unstable angina, (ii) peripheral arterial occlusion disease, (iii) coronary intervention (coronary artery dilation (PTCA), atherosclerosis (DCA), stent attraction) Post-stenosis, (iv) coronary-artery bypass surgery-post-stenosis (v) other peripheral artery interventions (angioplasty, atherosclerosis, stent transplantation, etc.) and post- bypass stenosis, ( vi) ischemic heart disease such as myocardial infarction, angina pectoris, (vii) intermittent claudication (viii) stroke (e.g., cerebral infarction, cerebral embolism, cerebral hemorrhage, etc.), (ix) tear infarction, (x) cerebrovascular dementia, (xi) Atherosclerosis (e.g., atherosclerosis, etc.) and diseases thereof (e.g., ischemic heart disease such as myocardial infarction, and cerebrovascular diseases such as cerebral infarction, stroke), (xii) heart failure, (xiii) arrhythmia, (xiv) atherosclerosis nidal development, (xv) thrombus formation, (xvi ) Hypotension, (xvii) shock, (xviii) vascular embolism due to shock (eg, disseminated intravascular coagulation (DIC), etc.)], in particular, atherosclerosis,

(3) respiratory diseases [respiratory distress syndrome, respiratory failure, emphysema, pneumonia, bronchial infection, bronchiolitis, etc.],

(4) osteoarthritis diseases (rheumatic arthritis, osteoporosis, osteomalacia, osteopenia, bone-Behcet's disease, etc.), in particular, rheumatoid arthritis,

(5) digestive, liver, gallbladder and pancreatic diseases (ulcerative colitis, gastritis, peptic ulcer, cirrhosis, liver failure, hepatitis, cholecystitis, pancreatitis, etc.), in particular, ulcerative colitis,

(6) renal-urinary tract diseases [nephritis, kidney failure, cystitis, etc.], or a combination of these diseases (multi-organ dysfunction, etc.). In addition, the compositions of the invention are useful for the prevention / treatment of infections as inhibitors of TLR signals, and especially of sepsis (severe sepsis) associated with organ failure caused by TLR signal changes.

The dosage of the composition of the present invention may vary depending on the type, age, weight and condition, dosage form, mode of administration and duration of the compound (particularly the compound of the present invention, its salts and prodrugs) that are stable in the acidic range, For example, the dosage is generally from about 0.01 to about 1000 mg / kg of compound (Iaa) or (Ie) of the invention per day in sepsis patients (adults weighing about 60 kg), preferably About 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, most preferably about 0.1 to about 50 mg / kg, and especially about 1.0 to about 30 mg / kg, The daily dose is administered intravenously either all at once or in several portions during the day. Alternatively, it can be administered continuously by intravenous dropping. Lower daily dosages may be sufficient, or additional dosages may be necessary because the dosage may vary depending on various factors as discussed above.

The composition of the present invention can be used simultaneously with, for example, a drug other than the compound of the present invention, or a salt thereof or a prodrug thereof.

Drugs that can be used simultaneously with the compounds of the present invention, their salts or prodrugs thereof (hereinafter, sometimes referred to simply as concomitant drugs) include, for example, antibacterial agents, antifungal agents, non-steroidal anti-inflammatory drugs, steroids, anticoagulants, platelets Anticoagulants, thrombolytic drugs, immunomodulators, antiprotozoal agents, antibiotics, antitussives and expectorant drugs, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, hypertensive diuretics, mental stabilizers, antipsychotics, antitumor drugs, hypotensive drugs, muscle Relaxants, anticonvulsants, antidepressants, antiallergic drugs, cardiovascular drugs, antiarrhythmic drugs, vasculature, vasoconstrictors, hypertensive diuretics, antidiabetic drugs, antagonists, vitamins, vitamin derivatives, arthritis drugs, antirheumatic drugs, antiasthma Drugs, urinary emptying / urinary incontinence medications, atopic dermatitis medications, allergic rhinitis medications, hypertension drugs, endotoxin-antagonists or -antibodies, The antibodies to inhibit inflammatory mediator activity - call transfer inhibitor, antibody to inhibit inflammatory mediator activity inhibitors, inflammatory mediator activity, anti-inflammatory mediator activity inhibitor, wherein. Among these, antibacterial agents, antifungal agents, non-steroidal anti-inflammatory drugs, steroids, anticoagulants and the like are preferable. Specific examples thereof include:

(1) antibacterial agents

<1> sulfa drug

Sulfamethazole, sulfisoxazole, sulfamomonotoxin, sulfamethiazole, sulfazol sulfapiridine, silver sulfadiazine and the like.

<2> quinoline antibacterial

Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, opfloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, spafloxacin, plexaxacin and the like.

<3> anti-tuberculosis agent

Isoniazid, etambutol (etatambutol hydrochloride), p-aminosalicylic acid (calcium p-aminosalicylate), pyrazineamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.

<4> anti-acidic bacterial drugs

Diaphenylsulfone, rifampicin and the like.

<5> antiviral drugs

Idocuridine, acyclovir, vidarabine, gancyclovir and the like.

<6> anti-HIV agents

Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.

<7> anti syphilis bacterium

<8> antibiotics

Tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibecacin, cannedomycin, libidomycin, tobramycin, amikacin, pradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline , Doxycycline, Ampicillin, Piperacillin, Ticacillin, Cephalotin, Sephapirine, Cephaloridine, Sephaclo, Cephalexin, Ceproxadine, Sephadroxil, Sephamandol, Celltocarcinoma, Cepuroxime, Cytima, Cell Tiam Hexetyl, Cefuroxime Axetyl, Cefdinir, Cefditorene Coated Room, Ceftazidim, Cefpyramid, Cefsulodin, Cefmenoxime, Cefpodoxyl Proxetyl, Cefpyrom, Cenzozofran, Cefepim, Cefsulodine, Cefmenoxime, Cefmethazole, Cefminox, Sepoxitine, Cefbuferazone, Latamoxef, Plomoxef, Cefazolin, Cytotaxime, Cefferazone, Cefti foot, Moxalactam, Thiena Mycin, liquor Pazecin, aztreonam or salts thereof, griseofulvin, lancassidin-group antibiotics (J. Antibiotics, 38, 877-885 (1985)) and the like.

(2) antifungal agents

<1> polyethylene antibiotics (eg, amphotericin B, nystatin, trichomycin)

<2> Griseofulvin, pyrronitrin, etc.

<3> cytosine metabolism antagonists (eg, flucytosine)

<4> imidazole derivatives (e.g., econazole, clotrimazole, myconazole nitrate, biponazole, croconazole)

<5> triazole derivatives (eg, fluconazole, itraconazole, azole compound [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3 -(1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3 (2H, 4H)- 1,2,4-triazolone]

<6> thiocarbamic acid derivatives (eg, trinaphthol)

<7> echinocandine derivatives (for example, capofungin, micapungin, anidulafungin) and the like.

(3) non-steroidal anti-inflammatory drugs

Acetaminophen, phenacetin, ethenamide, sulfinine, antipyrine, migrenin, aspirin, mephenamic acid, sulfenic acid, flufenamic acid, diclofenac sodium, roxofene sodium, phenylbutazone, indomethacin, ibuprofen, keto Propene, naproxen, oxaprozin, flubiprofen, fenbufen, pranoprofen, flocfenin, epirisol, tiaramid hydrochloride, zaltoprofen, gabexate mesylate, chamostat mesylate, uristatin , Colchicine, probenside, sulfinpyrazone, benzbromarone, allopurinol, gold sodium thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine , Pettidine, levfanol, ketoprofen, naproxen, oxymorphone or salts thereof.

(4) steroids

Dexmethasone, hexestrol, metimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluorinide, fluorinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone diclomethasone Cypionate, Estriol and the like.

(5) anticoagulants

Heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitors, antithrombin III, dalteparin sodium, warfarin potassium, agatroban, gabexate, sodium citrate and the like.

(6) platelet coagulation inhibitor

Ozagrerel sodium, ethyl isosafentate, veraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like.

(7) thrombolytic drugs

Tisokinase, urokinase, streptokinase and the like.

(8) immunomodulators

Cyclosporin, taclolimus, gusperimus, azathioprine, antilymphocyte serum, dry sulfonated immunoglobulins, erythropoietin, colony-stimulating factor, interleukin, interferon and the like.

(9) Antiprotozoal

Metronidazole, tinidazole, diethylcarbazine citrate, guinin hydrochloride, guinin sulfate, and the like.

(10) antitussive and expectorant drugs

Ephedrine hydrochloride, noscarpine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, alloclamide, clopedinol, picopridamine, Cloperastine, protochillol, isoproterenol, salbutamol, terbutalin, oxymethabuno, morphine hydrochloride, dextrometopan hydrobromide, oxycodone hydrochloride, dimemorphan phosphate, tifepidine hydride , Pentoxyberine citrate, clopedanol hydrochloride, benzonatate, guapenesine, brohexine hydrochloride, ambrosol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine and the like.

(11) sedatives

Clopromazine hydrochloride, atropine sulphate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamyral sodium, nitrazepam, estazollam, flurazzepam, haloxazolam, triazolam , Flunitrazepam, bromovaleric urea, chloral hydrate, triclophos sodium and the like.

(12) anesthetic

(12-1) Local Anesthetics

Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxetazaine and the like.

(12-2) General Anesthetic

<1> inhalation anesthetics (e.g. ether, halotane, nitric oxide, isoflurane, enflurane),

<2> intravenous anesthetics (for example, ketamine hydrochloride, dropperidol, thiopental sodium, thiamiral sodium, pentobarbital) and the like.

(13) anti-ulcer drugs

Metoclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pyrenzepine, cimetidine, ranitidine, pamotidine, eurogastron, oxetazaine, proglumide, omeprazole, sucralate, sulfide, setrec Cement, gephanate, aldioxa, tefrenone, prostaglandin and the like.

 (14) antiarrhythmics

<1> Na channel blockers (e.g., quinidine, procaineamide, disopyramid, azmalin, lidocaine, mexyltine, phenytoin),

<2> β-blockers (e.g., propanolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, catelol, arotinol),

<3> K channel blockers (eg amiodarone),

Ca channel blockers (eg verapamil, diltiazem) and the like.

(15) hypertensive diuretics

Hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic acid, bumethanide, meproside, azocemide, spironolactone, potassium canrenoids, tri Amterene, amylolide, acetazolamide, D-mannitol, isosorbide, aminophylline and the like.

(16) mental stabilizers

Diazepam, rolazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, clocksazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.

(17) antipsychotics

Chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine, thiolidazine hydrochloride, perphenazine maleate, flufenazine maleate, procloperazine maleate, levomeproazine maleate, prometha Gin hydrochloride, haloperidol, bromperidol, spiferon, recepin, clocapramine dihydrochloride, sulfide, jotepin and the like.

(18) antitumor drugs

6-O- (N-chloroacetylcarbamoyl) fumagilol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarcinostatin, cytosine arabinoside, fluorouracil , Tetrahydrofuryl-5-fluorouracil, pisivanyl, lentinan, levamisol, bestatin, azimexone, glycidazine, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate , Vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafu, Camofu, Cytarabine, Methyltestosterone, Testosterone Propionate, Testosterone Enanthate, Mepiostane, Phestostol, Cleat Romadinon acetate, lowproline acetate, buserelin acetate, and the like.

(19) hypolipidemic drugs

Clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate (Chem. Pharm. Bull, 38, 2792-2796 (1990)), pravastatin, simvastatin Probucol, bezafibrate, clinofibrate, nicomol, cholestilamine, dextran sulfate sodium and the like.

20 muscle relaxants

Pridinol, tubokurarin, pancuronium, tolverison hydrochloride, clofenesin carbamate, baclofen, clomezanone, mephenesin, cloxazone, eperison, tizanidine and the like.

(21) Anticonvulsant

Phenytoin, ethosuccimid, acetazolamide, clodiazepoxide, trimetadione, carbazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.

(22) antidepressants

Imipramine, clomipramine, nocifthilin, phenelzin, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, myanserine hydrochloride, mapproline hydrochloride, sulfides, fluvoxamine Maleate, trazodone hydrochloride and the like.

(23) Antiallergic Drugs

Diphenhydramine, clofeniramine, tripelinamine, methodylamin, clemizole, diphenylpyralline, methoxyphenamine, disodium chromoglycate, tranilast, repirinast, amlexoxox, ibudilast Ketotifen, terpenadine, mequitazine, azelastine, efinastin, ozagrel hydrochloride, praclast hydrate, ceratlast and the like.

(24) strong heart

Trans-Bioxocampo, Terepilol, Aminophylline, Ethylephrine, Dopamine, Dobutamine, Denophamine, Aminophylline, Vesnarine, Amlinone, Pimovendan, Uvidecarenone, Digitoxin, Digoxin, Methyldigoxin, Lanatoside C, G-stropantin and the like.

(25) angioplasty

Oxypedrine, diltiazem, tolazoline, hexobendine, methane, clonidine, methyldopa, guanabenz and the like.

(26) vasoconstrictor

Dopamine, dobutamine, denophamine, etc.

(27) hypertensive diuretics

Hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.

(28) antidiabetic drugs

Tolbutamide, clopropamide, acetohexamide, glybenclamide, tolazamide, acarbose, epalestat, troglitazone, glucagon, glymidine, glyphzide, phenfomin, buformin, metformin and the like.

(29) anti-narcotics

Levalophane, nalopins, naloxone or salts thereof.

30 fat-soluble vitamins

<1> vitamin A: vitamin A ₁ , vitamin A ₂ and retinol palmitate

<2> Vitamin D: Vitamin D ₁ , D ₂ , D ₃ , D ₄ and D ₅

<3> Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate

<4> Vitamin K: Vitamin K ₁ , K ₂ , K ₃ and K ₄

<5> folic acid (vitamin M) and the like.

(31) Vitamin Derivatives

Various derivatives of vitamins, for example vitamin D ₃ derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol and the like, 5, Vitamin D ₂ derivatives such as 6-trans-ergocalciferol and the like.

(32) anti-asthma drugs

Isoprelinine hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride, tulobuterol hydrochloride, orcifrelin sulfate, phenoterol hydrobromide, ephedrine hydrochloride Ipratropium bromide, oxytropium bromide, flutropium bromide, theophylline, aminophylline, disodium chromoglycate, transanilast, repirinast, anlexanone, ibudilast, ketotifen, terpenadine, Mequitazine, azelastine, epinastine, ozagarel hydrochloride, praclast hydrate, cerastast, dexamethasone, prednisone, hydrocortisone, beclomethaneson dipropionate and the like.

(33) Urinary Emptying / Urinary Incontinence Therapeutics

Flaboxate hydrochloride and the like.

(34) atopic dermatitis

Disodium chromoglycate and the like.

(35) Allergic Rhinitis

Disodium chromoglycate, clofeniramine maleate, alimethazine tartrate, clemastine fumarate, homoclocycline hydrochloride, terpenadine, mequitazine and the like.

36 hypertension drugs

Dopamine, dobutamine, denophamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-stropantin and the like.

(37) other

Hydroxycampa, diaserine, megestrol acetate, nicerologoline, prostaglandin and the like.

The combined use of a compound of the present invention, or a salt thereof or a prodrug thereof and a combination drug provides the following effects.

(1) The dosage of the compounds of the present invention, salts thereof and prodrugs thereof may be reduced than in the case of single administration of the compounds of the present invention, or salts thereof or prodrugs thereof.

(2) The synergistic effect of the above-mentioned sepsis, septic shock, inflammatory disease, infectious disease and the like can be achieved.

(3) A wide range of therapeutic effects can be achieved for various diseases caused in connection with viral infections and the like.

Regarding the use of the compound of the present invention, or a salt thereof, or a prodrug thereof and a combination drug, the compound of the present invention, or a salt thereof, or a prodrug thereof and a concomitant drug has no limitation at the time of administration, or a compound of the present invention. , Salts thereof or prodrugs thereof, and concomitant drugs can be administered simultaneously to the subject to be administered, or can be administered at staggered times. The dosage of the concomitant drug depends on the clinical dosage and can be appropriately determined depending on the administration target, the route of administration, the disease, the combination, and the like.

The dosage form of the compound of the present invention, the salt thereof or the prodrug thereof and the concomitant drug is not particularly limited as long as the compound, the salt thereof, or the prodrug thereof and the concomitant drug are used for administration. Such dosage forms vary depending on the type of concomitant drug and the like, for example (1) administration of an agent obtained by simultaneous addition of a compound of the present invention, a salt thereof or a prodrug thereof and a concomitant drug, (2) Simultaneous administration by a single route of administration of two types of preparations obtained by separate preparation of the pharmaceutical composition of the composition and the concomitant drug, (3) obtained by the separate preparation of the pharmaceutical composition of the composition of the invention and the concomitant drug Chronological administration of two types of formulations by a single route of administration, (4) simultaneous administration by different routes of administration of two types of formulations obtained by separate preparation of a pharmaceutical composition of a composition of the present invention and a combination drug, ( 5) timed administration by different routes of administration of the two types of preparations obtained by separate preparation of the pharmaceutical compositions of the compositions of the invention and the concomitant drug (e.g., compositions of the invention, Then the order of administering the pharmaceutical composition of the concomitant drug, or vice versa.

The toxicity of the pharmaceutical composition of the concomitant drug is low and, for example, by combining the concomitant drug with a pharmaceutically acceptable carrier according to known methods per se, oral or parenteral (eg, topical, rectal or intravenous). Intra-dosing) Obtain pharmaceutical compositions such as tablets for administration (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, and the like, and stably May be administered. Injections can be administered intratracheally, intravenously, intramuscularly, subcutaneously, or directly into the lesion.

As pharmacologically acceptable carriers useful in the preparation of pharmaceutical compositions of concomitant drugs, various conventional organic or inorganic carriers are mentioned as materials for preparation. Examples thereof include excipients, lubricants, binders and disintegrants for solid preparations, and solvents, dissolution aids, suspending agents, isotonic and smoothing agents for liquid preparations. If necessary, conventional additives such as preservatives, antioxidants, colorants, sweeteners, absorbents, moisture agents and the like may be suitably used in suitable amounts.

As excipients, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, hard silicic acid and the like are mentioned.

As lubricants, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are mentioned.

As the binder, for example, crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidine, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium And the like are mentioned.

As disintegrating agents, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like are mentioned.

As the solvent, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like are mentioned.

As dissolution aids, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are mentioned.

As the suspending agent, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; Mention is made of hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidine, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

As isotonic agents, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like are mentioned.

As the smoothing agent, for example, benzyl alcohol and the like are mentioned.

As preservatives, for example, p-oxybezoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are mentioned.

As antioxidants, for example, sulfite, ascorbic acid, α-tocopherol and the like are mentioned.

When the concomitant drug is added to the composition of the present invention, the amount of the concomitant drug may be appropriately determined depending on the administration target, the route of administration, the disease, and the like, and may be adjusted like the compound of the present invention, salts thereof and prodrugs thereof.

When the pharmaceutical composition of the composition of the present invention and the concomitant drug is used in combination, the content of the concomitant drug in the pharmaceutical composition of the concomitant drug may be appropriately determined depending on the administration target, administration route, disease, and the like. The dosage is generally from 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight, more preferably from about 0.5 to 20% by weight, based on the total formulation.

The content of an additive such as a carrier in the pharmaceutical composition of the concomitant drug varies depending on the form of the preparation. The content is generally about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total formulation.

Pharmaceutical compositions of concomitant drugs can be prepared by known methods in which generally known methods of preparation are used.

For example, the concomitant drug may be a dispersant (e.g., Tween 80 (ATLASPOWDER, USA), HCO60 (NIKKO CHEMICALS), polyethylene glycol, carboxymethylcellulose, sodium arginate, hydroxypropylmethylcellulose, dextrin, etc.) Topical agents (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), isotonic agents (eg, For example, sodium chloride, potassium chloride, mannitol, sorbitol, glucose and the like), pH adjusters (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl p-hydroxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (e.g. For example, concentrated glycerin, meglumine, etc.), dissolution aids (e.g., propylene glycol, sucrose, etc.), smoothing agents (e.g., glucose, benzyl alcohol, etc.) and the like. , Vegetable oils or by dissolving, suspending or emulsifying in a solubilizing agent such as (e. G., Olive oil, sesame oil, myeonssi oil, corn oil or the like) or propylene glycol to form an oil-based injection formulation.

In addition, the concomitant drug may be used in place of the compound of the present invention, a salt thereof, or a prodrug thereof to provide an injectable emulsion composition of the present invention.

Oral formulations may be used as appropriate, including excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose). , A generally known method of compressing the concomitant drug by adding polyvinyl pyrrolidine, hydroxypropyl cellulose and the like or a lubricant (e.g. talc, magnesium stearate, polyethylene glycol 6000, etc.), followed by taste Or to form an enteric coating, or by known coating methods per se to achieve sustained release. Such coatings are, if appropriate, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose Acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, Eudradide (copolymer of ROHME, Germany, methacrylic acid and acrylic acid), dyes (e.g. iron with iron, titanium oxide, etc.) Can be). Formulations for oral administration may be immediate release formulations or sustained release formulations.

For example, when suppositories are prepared, the concomitant drug may also be formulated as an oily or aqueous solid or semisolid or liquid suppository by known methods per se. Oil-based suppository bases, if appropriate, include, for example, higher fatty glycerides (eg, cocoa butter, WITEPSOL (DYNAMIT NOBEL, Germany), etc.), intermediate fatty acids (eg, MYGLYOL (DYNAMIT NOBEL, Germany), etc. ), Or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like. The aqueous base can be, for example, polyethylene glycol or propylene glycol, and the aqueous gel base can be, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic polymers and the like.

Examples of the above-mentioned sustained-release preparations include sustained-release microcapsules and the like.

Sustained release microcapsules can be prepared by known methods per se, for example, sustained release formulations shown below [2] are preferably formed and administered.

The concomitant drug may be formulated as an oral dosage form such as a solid preparation (eg, powders, granules, tablets, and capsules), or a rectal dosage form such as suppositories, depending on the type of drug.

In the following, [1] infusion and preparation of the concomitant drug, [2] sustained release or immediate release preparation of the concomitant drug and the preparation thereof, and [3] sublingual tablet of the concomitant drug, buccal or buccal rapid disintegrating agent and the preparation thereof Is described in detail.

[1] injection solutions and preparation thereof

Injection solutions containing a concomitant drug dissolved in water are preferred. Injection solutions may contain benzoate and / or salicylate.

Injection solutions are obtained by dissolving both the concomitant drug and, if necessary, both benzoate and / or salicylate in water.

Salts of the above-mentioned benzoic acid and salicylic acid include, for example, alkali metal salts such as sodium, potassium, and the like, alkaline earth metal salts such as calcium, magnesium, and the like, organic acid salts such as ammonium salt, meglumine salt, tromethanol, and the like.

The concentration of the concomitant drug in the injection solution is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of benzoate and / or salicylate is preferably 0.5 to 50 w / v%, more preferably 3 to 20 w / v%.

Injection solutions include stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), isotonic agents (E.g., sodium chloride, potassium chloride, etc.), dispersant (e.g., hydroxypropylmethylcellulose, dextrin), pH adjuster (hydrochloric acid, sodium hydroxide, etc.), preservative (ethyl p-oxybenzoate, benzoic acid, etc.), solubilizer Commonly used in injection solutions such as (eg, concentrated glycerin, meglumine, etc.), dissolution aids (eg, propylene glycol, sucrose, etc.), smoothing agents (eg, glucose, benzyl alcohol, etc.). It may contain an additive suitably. These additives are added in fractions commonly used in injection solutions.

Injectable solutions can be obtained by dissolving the concomitant drug and, if necessary, both benzoate and / or salicylate, and, if necessary, the above-mentioned additives in water. These may be dissolved in any order in a suitable manner in the usual product of the injection solution.

The injection aqueous solution is preferably heated and subjected to, for example, sterilization by filtration, high pressure sterilization by heating, and the like in the same manner as a usual injection liquid to provide an injection liquid.

The aqueous injection solution is preferably subjected to autoclaving, for example, by heating at 100 ° C. to 121 ° C. for 5 to 30 minutes.

It can be prepared as an antibacterial solution and can be used as a formulation for multiple subseparated administrations.

[2] sustained release or immediate release preparations and preparations thereof

Preference is given to sustained release preparations in which the core containing the concomitant drug is covered with a film former such as an insoluble substance, a swellable polymer, or the like as desired. For example, sustained release preparations that are administered orally once a day are preferred.

Insoluble materials used in film formers include, for example, cellulose ethers such as ethylcellulose, butylcellulose and the like; Cellulose esters such as cellulose acetate, cellulose propionate and the like; Polyvinyl esters such as poly (vinyl acetate), poly (vinyl butyrate) and the like; Acrylic acid / methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, alkyl methacrylate Acrylic polymers such as copolymers, poly (methyl methacrylate), polymethacrylates, polymethacryl amides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydrides) and glycidyl methacrylate copolymers, in particular Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (Ethyl acrylate methyl methacrylate ethyl methacrylate trimethylammonium chloride copolymer), Eudragit NE-30D Eudragits (Rohm Pharma) etc., such as (methyl methacrylate ethyl acrylate copolymer) etc .; Hydrogenated oils such as hydrogenated castor oil (eg, Lovely Wax (Freund Inc.)) and the like; Waxes such as brazilian lead palm, fatty acid glycerine ester, paraffin and the like; Polyglycerin fatty acid esters and the like.

As swellable polymers, polymers having acidic dissociation groups that exhibit pH-dependent swelling are preferred, and polymers with acidic dissociation groups that seldom swell in the acidic range, such as the stomach, but not in the neutral range, such as the small intestine and the large intestine. Is preferred.

Examples of polymers having acidic dissociation groups showing pH-dependent swelling are Carbomer 934P, 940, 941, 974P, 980, 1342, etc., polycarbophil, calcium polycarbophil (all mentioned above are products of BF Goodrich), HI -BIS-WAKO 103, 104, 105, 304 (all are products of Waco Pure Chemicals Industries, Ltd.) and the like.

The film former used in the sustained release formulation may further contain a hydrophilic substance.

Examples of hydrophilic substances include polysaccharides optionally having sulfuric acid groups such as pullulan, dextrin, alkali metal salts of alginic acid, and the like; Polysaccharides having a hydroxy alkyl group or a carboxy alkyl group such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium and the like; Methylcellulose, polyvinylpyrrolidine, polyvinyl alcohol, polyethylene glycol, and the like.

The content of the insoluble substance in the film forming agent for the sustained release formulation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75% ( w / w), and the content of the swellable polymer is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The film former may further contain a hydrophilic material, in which case the content of hydrophilic material for the film former is up to about 50% (w / w), preferably about 5 to about 40% (w / w) , More preferably about 5 to about 35% (w / w). As used herein, the above-mentioned% (w / w) is weight percent relative to the film former composition wherein the solvent (eg, lower alcohol such as water, methanol, ethanol, etc.) has been removed from the film forming liquid formulation. to be.

Sustained release formulations are film forming liquid formulations prepared by preparing a core containing a drug and dissolving, dissolving or dispersing the insoluble material, the swellable polymer, and the like in a solvent by heating, as exemplarily mentioned below. It is prepared by coating the resulting core.

I. Preparation of Cores Containing Drugs

The form of the core containing the drug coated with the film former (hereinafter, sometimes simply referred to as the core) is not particularly limited, but is preferably formed of particles such as granules, granulated granules and the like.

When the core is made of granules or granulated granules, its average particle size is preferably about 150 to 2,000 μm, more preferably about 500 to about 1,400 μm.

The core can be manufactured by a typical manufacturing method. For example, the drug is mixed with suitable excipients, binders, disintegrants, lubricants, stabilizers and the like and subjected to wet compression granulation, fluid bed granulation and the like.

The drug content of the core is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w).

Examples of excipients contained in the core include saccharides such as starch, crystalline cellulose, calcium phosphate, corn starch and the like, sucrose, lactose, mannitol, glucose and the like. Of these, crystalline cellulose and corn starch are preferred.

Examples of binders include polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidine, Pluronic F68, gum arabic, gelatin, starch and the like. Examples of disintegrants include carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidine (Crospovidone), low substituted hydroxypropylcellulose (L-HPC), and the like. do. Of these, hydroxypropylcellulose, polyvinylpyrrolidine and low substituted hydroxypropylcellulose are preferred. Examples of lubricants and anticoagulants include talc, magnesium stearate and inorganic salts thereof, and examples of lubricants include polyethylene glycol and the like. Examples of stabilizers include acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, and the like.

The core can also, for example, spray a dissolved binder in a suitable solvent, such as water, lower alcohols (eg, methanol, ethanol, etc.), on top of the inert carrier particles that are the center of the core, in addition to the above-mentioned manufacturing methods, for example , Drugs or a mixture of drugs and excipients, lubricants and the like can be prepared by rolling granulation, pan coating method, fluidized bed coating method or melt granulation method. Examples of inert carrier particles include those made from sucrose, lactose, starch, crystalline cellulose and waxes, and their average particle size is preferably from about 100 μm to about 1,500 μm.

In order to separate the drug contained in the core of the film former, the surface of the core may be coated with a protective agent. Examples of protecting agents include the aforementioned hydrophilic materials, insoluble materials and the like. As the protective agent, polysaccharides preferably having polyethylene glycol, hydroxy alkyl groups or carboxy alkyl groups are used, more preferably hydroxypropylmethylcellulose and hydroxypropylcellulose. The protecting agent may contain a lubricant such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, and the like, as a stabilizer, and talc. When a protective agent is used, the amount to be coated is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (relative to the core) w / w).

Protective agents can be coated by conventional coating methods. Specifically, the protective agent is spray-coated to the core by, for example, a fluidized bed coating method, a fan coating method, or the like.

II. Core coating with film former

The core obtained in I as described above is coated with a film-forming liquid formulation prepared by dissolving, dissolving or dispersing the aforementioned insoluble substance, pH-dependent swellable polymer, and hydrophilic substance in a solvent by heating to form a sustained release formulation. to provide.

To coat the film forming liquid formulation on the core, for example, a spray coating method or the like can be applied.

The composition ratio in the film forming liquid formulation of the insoluble material, the swellable polymer or the hydrophilic material is suitably determined to bring the content of each component of the coating film to the above-mentioned content.

The coating amount of the film former is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably about 5 to 35% (w / to the core). w) (except coating amount of protective agent).

As solvents for film forming liquid formulations, water and organic solvents may be used alone or in a mixture of both. The mixing ratio (water / organic solvent: weight ratio) of water and organic solvent in the mixture may vary within the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves the insoluble substance. For example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like, lower alkanols such as acetone and the like, acetonitrile, chloroform, methylene chloride and the like are used. Among them, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as the solvent of the film former. If desired, the film forming liquid formulation may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid and the like for stabilization of the film forming liquid formulation.

When spray coating is applied, the method follows a conventional coating method, which is a method of specifically spray coating a film forming liquid formulation to a core, such as a fluidized bed coating method, a pan coating method, or the like. If desired, talc, titanium oxide, magnesium stearate, calcium stearate, light silicic anhydride and the like can be added as lubricants, glycerin fatty acid esters, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol and the like. It can be added as a plasticizer.

After coating of the film former, an antistatic agent such as talc or the like may be added if necessary.

Immediate release preparations may be liquid (solutions, suspensions, emulsions, etc.) or solids (granules, pills, tablets, etc.). On the other hand, oral administrations, and parenteral administrations such as injection solution and the like are used, oral administration is preferred.

Immediate release preparations may generally contain carriers, additives and excipients (hereinafter, often referred to simply as excipients) in addition to drugs which are active ingredients commonly used in the formulation art. Formulation excipients are not particularly limited as long as they are conventionally used as excipients for formulation. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Corporation, Avicel PH101, etc.), powdered sugars, granulated sugars, mannitol, hard silicic anhydride, magnesium carbonate, calcium carbonate Carbonate, L-cysteine and the like, preferably corn starch and mannitol and the like. These excipients may be used alone or in combination. The content of excipients is, for example, from about 4.5 to about 99.4 w / w%, preferably from about 20 to about 98.5 w / w%, more preferably from about 30 to about 97 w / relative to the total amount of the immediate release preparation. w%.

The drug content of the immediate release preparation is suitably determined in the range of about 0.5 to about 95%, preferably about 1 to about 60%, relative to the total amount of the rapid release preparation.

If the immediate release preparation is an oral solid preparation, it generally contains a disintegrant in addition to the above-mentioned ingredients. Examples of disintegrants include calcium carboxymethylcellulose (manufactured by Gotoku Yakuhin, ECG-505), croscarmellose sodium (e.g. Asahi Kasei Corporation, Actisol), crospovidone (e.g. Colicone CL, BASF) , Low substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsutani Chemical Industry Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo, Exprotab), partial α starch (PCS , Asahi Kasei Corporation). For example, when contacted with water or the like, those capable of disintegrating, swelling the granules by water absorption and forming a channel between the active ingredient and the excipient constituting the core may be used. These disintegrants may be used alone or in combination. The amount of disintegrant is appropriately determined according to the type and amount of the concomitant drug used, the design of the release formulation, and the like. The amount is generally about 0.05 to about 30 w / w%, preferably about 0.5 to about 15 w / w%, relative to the total amount of the immediate release formulation.

If the immediate release preparation is an oral solid preparation, the oral solid preparation may further contain, in addition to the above-mentioned compositions, the usual additives used in the solid preparation, if necessary. Examples of additives include binders (eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidine, pullulan, dextrin, etc.), Lubricants (e.g. polyethylene glycol, magnesium stearate, talc, hard silicic anhydrides (e.g. Aerosil (Nippon Aerosil)), surfactants (e.g. anionic surfactants such as sodium alkylsulfate, polyoxy Non-ionic surfactants such as ethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (e.g., synthetic pigments, caramel, red iron oxide, titanium oxide, riboflavin), if necessary , Corrective agents (e.g., sweeteners, fragrances, etc.), absorbents, preservatives, wetting agents, antistatic agents, etc. As stabilizers, LE is an organic acid, such as tar acid, citric acid, succinic acid, fumaric acid may be added.

Examples of the above-mentioned binders preferably include hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidine and the like.

Immediate release formulations may be prepared by mixing, as necessary, further kneading and forming each of the components described above, based on conventional manufacturing methods. The above-mentioned mixing can be carried out by conventional methods such as mixing, kneading and the like. Specifically, for example, when the rapid-release preparation is formed into particles, an upright granulator, a universal kneader (manufactured by Hata Tekkosho), a fluidized bed granulator FD-5S (Powrex Corporation), and the like are used for mixing, followed by wet extruded granules. By granulation, fluidized bed granulation or the like, so that the formulation is obtained as in the preparation of the core of the sustained release formulation described above.

The immediate release preparations and sustained release preparations thus obtained can be used by themselves. Alternatively, it may be administered simultaneously or at any interval of administration after suitable separate preparations with excipients for the preparation according to the usual methods and the like. Alternatively, if appropriate, together with excipients for preparation or the like, it may be prepared in a single preparation for oral administration (eg granules, granulated granules, tablets, capsules, etc.). The two formulations are converted into granules or granular granules and filled in a single capsule or the like to obtain a formulation for oral administration.

[3] sublingual tablets, buccal or buccal disintegrating agents and preparations thereof

Sublingual tablets, buccal formulations and oral immediate disintegrators may be solid formulations such as tablets or oral mucosal stenosis tablets (films).

As sublingual tablets, buccal or buccal disintegrating agents, preparations containing combination drugs and excipients are preferred. Adjuvants such as lubricants, isotonic agents, hydrophilic carriers, water dispersible polymers, stabilizers and the like. For easy absorption and enhanced bioavailability, β-cyclodextrin or β-cyclodextrin derivatives (eg, hydroxypropyl-β-cyclodextrin, etc.) may be contained.

Examples of the aforementioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, hard silicic anhydride, and the like. Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica and the like, with magnesium stearate and colloidal silica being particularly preferred. Examples of isotonic agents include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea, and the like, with mannitol being particularly preferred. Examples of hydrophilic carriers include swellable hydrophilic carriers such as crystalline cellulose, ethylcellulose, crosslinked polyvinylpyrrolidine, hard anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and the like, and especially crystalline cellulose (eg, Microcrystalline cellulose and the like). Examples of water dispersible polymers include gums (eg gum tragacanth, acacia gum, guar gum), alginates (eg sodium alginate), cellulose derivatives (eg methylcellulose, carboxymethylcellulose , Hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, water soluble starch, polyacrylic acid (e.g. carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrroli Dine, polycarbophil, ascorbate, palmitate and the like, and hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidine, polyethylene glycol and the like are preferred. In particular, hydroxypropylmethylcellulose is preferable. Examples of stabilizers include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, with citric acid and ascorbic acid being particularly preferred.

Sublingual tablets, buccal and oral immediate disintegrating agents can be prepared by mixing the combination drug and excipients by known methods per se. If desired, the aforementioned auxiliaries may be contained such as lubricants, isotonic agents, hydrophilic carriers, water dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like. After the above-mentioned components are mixed simultaneously or over time, the mixture is compartmentalized under pressure to give sublingual tablets, ball tablets or oral immediate disintegration tablets. To achieve a suitable hardness, solvents such as water, alcohols and the like are used to wet or wet, if necessary, before and after the formation of the compartment. After formation, the tablets are dried.

When mucoadsorbent tablets (films) are produced, the concomitant drug and the aforementioned water dispersible polymers (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients and the like are dissolved in a solvent such as water and obtained The solution is cast to obtain a film. In addition, additives such as plasticizers, stabilizers, antioxidants, preservatives, colorants, sweeteners and the like may be added. To impart suitable flexibility to the film, glycols such as polyethylene glycol, propylene glycol, and the like can be added, and bioadhesive polymers (e.g., polycarbophil, carbo) to increase the adsorption of the film to the oral mucosa lines. Botol) can be added. Casting pours the solution onto a non-adhesive surface, spreads the solution to a constant thickness (preferably about 10 to 1000 μm) using a coating equipment such as a doctor blade or the like, and dries the solution to obtain a film. The film thus formed can be dried at room temperature or under heating and cut into the desired surface area.

Examples of preferred oral immediate disintegrating agents are solid immediate dispersible administrations having a net structure of the concomitant drug and a water-soluble or water-diffusing carrier inert to the concomitant drug. The net structure can be obtained by evaporating the solvent from a solid composition consisting of a solution and a carrier obtained by dissolving the concomitant drug in a suitable solvent.

The composition of the oral immediate disintegrating agent preferably contains, in addition to the concomitant drug, a matrix former and a second component.

Examples of matrix formers include vegetable or animal proteins such as gelatin, dextrin, soybean, wheat, psyllium seed protein and the like; Rubber components such as gum arabic, guar gum, agar and pellets; Polysaccharides; Alginic acid; Carboxymethyl cellulose; Carrageenan; Dextran; Pectin; Synthetic polymers such as polyvinylpyrrolidine and the like; Substances derived from gelatin-arag gum complex and the like. Saccharides such as mannitol, dextrose, lactose, galactose, trehalose and the like; Cyclic saccharides such as cyclodextrin and the like; Inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate and the like; Amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine and the like are exemplified.

It is possible to introduce one or more matrix formers into solution or suspension prior to making into a solid. Such matrix formers may be present with or without a surfactant. Matrix formers may form the matrix and may also help to maintain the diffusion of the compound or combination drug of the invention in solution or suspension.

The composition may contain second components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavors, sweeteners, flavoring reagents and the like. Examples of suitable colorants include red, black and yellow iron oxides and FD & C blue NO. 2, FD & C red No. 40, such as Elis and Eberald's FD & C dyes. Suitable flavorings include mint, raspberries, licorice, oranges, lemons, grapes, caramels, vanilla, cherries, grape flavors and combinations thereof. Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K, taumartin and the like. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin containing compounds, adsorbent components and microencapsulated apomorphine.

The formulations generally contain the concomitant drug in a proportion of about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, and about 1 minute to about 60 minutes, preferably about 1 minute to about 15 minutes More preferably, a formulation capable of dissolving at least 90% of the concomitant drug in water for about 2 minutes to about 5 minutes (agents such as the sublingual tablets, ball formulations, etc. described above), and 1 to 60 seconds after being placed in the oral cavity, Preference is given to oral immediate disintegrating agents which preferably disintegrate in 1 to 30 sec, more preferably in 1 to 10 seconds.

The content of the aforementioned excipients in the total formulation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivatives relative to the total formulation is 0 to about 30% by weight. The amount of lubricant relative to the total formulation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of isotonic agents relative to the total formulation is about 0.1 to about 90 weight percent, preferably about 10 to about 70 weight percent. The amount of hydrophilic carrier for the total formulation is about 0.1 to about 50 weight percent, preferably about 10 to about 30 weight percent. The content of the water dispersible polymer relative to the total formulation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of stabilizer relative to the total formulation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The formulations described above may contain additives such as colorants, sweeteners, preservatives and the like if desired.

The dosage of the pharmaceutical composition of the concomitant drug varies depending on the type of concomitant drug, the age, weight and condition of the patient, the dosage form, the mode of administration and the duration, while the amount of the concomitant drug may be, for example, the patient (weight about 60 kg Phosphorus adult) per day, generally about 0.01 to about 1000 mg / kg, preferably about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 100 mg / kg, most preferably about 0.1 To about 50 mg / kg, in particular about 1.5 to about 30 mg / kg, wherein the daily dose may be administered intravenously all at once or divided into several portions during the day. It is also true that lower daily dosages may be sufficient or more than may be needed, since dosages may vary depending on various factors as discussed above.

The concomitant drug may be contained in any amount so long as the side effect does not cause a problem. The daily dose of the concomitant drug may vary and is not limited depending on the disease state, age, sex, weight and sensitivity of the subject administered, the time and interval of administration, the nature, dispersibility and type of the pharmaceutical preparation, the type of active ingredient, etc. On the other hand, the amount of the drug is generally about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg of body weight of the mammal by oral administration, and the amount is generally at one time during the day. All or dividedly two to four times.

If the compositions of the invention and the pharmaceutical compositions of the concomitant drug are administered simultaneously, they may be administered simultaneously, or the pharmaceutical compositions of the concomitant drugs may be administered first, followed by the compositions of the invention. Alternatively, the composition of the present invention may be administered first, followed by the pharmaceutical composition of the concomitant drug. For timed administration, the time difference varies depending on the active ingredient administered, the dosage form and the route of administration. For example, when the pharmaceutical composition of the concomitant drug is administered first, the composition of the present invention is more preferably within 1 minute to 3 days, preferably within 10 minutes to 1 day, more preferably after the pharmaceutical composition of the concomitant drug is administered. Preferably within 15 minutes to 1 hour. When the composition of the present invention is administered first, the pharmaceutical composition of the concomitant drug is within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 after the composition of the present invention is administered. Is administered in time.

Next, the present invention is further explained with reference to reference examples, examples and comparative examples. The following examples and the like illustrate the invention, but the invention is not so limited.

¹ H NMR spectra were measured with a VARIAN GEMINI 200 (200 MHz) spectrometer using tetramethyl silane as internal reference and expressed as total δ value in ppm. When a solvent mixture is applied, the number in [()] is the volume ratio of each solvent. Unless otherwise specified, A% is by weight. The proportion of solvent in chromatography on silica gel is the volume ratio of the solvents to be mixed.

High polar diastereomer means a diastereomer having a smaller Rf value when measured by normal thin layer chromatography under the same conditions (eg using ethyl acetate / hexane as eluent), whereas a low polar moiety Stereoisomers refer to diastereomers having a larger Rf value in the measurement.

The meanings of the abbreviations used in the examples are as follows:

s: single d: double t: triple q: quad

dd: double double tt: triple triple m: multi

br: broad J: coupling constants

Reference Example A mentioned below may be produced according to the reference example of WO99 / 46424, and Reference Example B may be generated according to the embodiment of WO99 / 46424.

Reference Example A

Reference Example A1 Ethyl 2-sulfo-1-cyclohexene-1-carboxylate

Reference Example A2 Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate

Reference Example A3 Ethyl 2-chlorosulfonyl-1-cyclopentene-carboxylate

Reference Example A4 Ethyl 2-chlorosulfonyl-1-cycloheptene-1-carboxylate

Reference Example A5 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid sodium salt

Reference Example A6 1- (3-fluoro-4-nitrophenyl) -1H-1,2,4-triazole

Reference Example A7 1- (4-amino-3-fluorophenyl) -1H-1,2,4-triazole

Reference Example A8 Methyl 4-benzyloxycarbonylamino-3-chlorobenzoate

Reference Example A9 4-benzyloxycarbonylamino-3-chlorobenzoic acid

Reference Example A10 tert-Butyl N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) glycinate

Reference Example A11 tert-butyl N- (4-amino-3-chlorobenzoyl) glycinate

Reference Example A12 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid

Reference Example A13 Ethyl 2-mercapto-5-phenyl-1-cyclohexene-1-carboxylate

Reference Example A14 Ethyl 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate

Reference Example A15 Ethyl 5-tert-butyl-2-mercapto-L-cyclohexene-1-carboxylate

Reference Example A16 Ethyl 5-tert-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate

Reference Example A17 Ethyl 5,5-dimethyl-2-mercapto-1-cyclohexene-1-carboxylate

Reference Example A18 Ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate

Reference Example B

Reference Example B1 Ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 1)

Reference Example B2 Ethyl 6- [N- (4-chloro-2-fluorophenyl) -N-methylsulfamoyl] -1-cyclohexene-1-carboxylate (Compound 2)

Reference Example B3 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 3)

Reference Example B4 Ethyl 6- [N- (2,6-diisopropylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 4)

Reference Example B5 Ethyl 6- [N- (4-nitrophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 5)

Reference Example B6 Ethyl 6- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 6)

Ethyl 2- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 7)

Reference Example B7 Ethyl 2- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 9)

Reference Example B8 2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1,2-benzoisothiazol-3 (2H) -one 1,1-dioxide (Compound 67)

Ethyl 2- [N- (4-methoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 8)

Reference Example B9 Ethyl 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 10)

Reference Example B10 Ethyl 6- [N- (3-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 11)

Reference Example B11 2- (4-Fluorophenyl) -4,5,6,7-tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (Compound 68)

Ethyl 6- [N- (4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 12)

Ethyl 2- [N- (4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 18)

Reference Example B12 Ethyl 6- [N- (2,6-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 13)

Reference Example B13 Ethyl 6- [N- (2,3-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 14)

Reference Example B14 Ethyl 6- [N- (2,5-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 15)

Reference Example B15 Ethyl 6- [N- (3,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 16)

Reference Example B16 Ethyl 6- [N- (3,5-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 17)

Reference Example B17 1-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 19)

d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (d-ethyl 6- [N- (2,4-difluorophenyl) Sulfamoyl] cyclohex-1-ene1-carboxylate) (Compound 20)

Reference Example B18 Ethyl 6- [N- (2-ethoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 21)

Reference Example B19 Methyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 22)

Reference Example B20 Propyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 23)

Reference Example B21 Methyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 24)

Reference Example B22 Isopropyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 25)

Reference Example B23 Ethyl 6- [N- (2-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 26)

Reference Example B24 Ethyl 6- [N- (2-fluoro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 27)

Reference Example B25 Ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclohex-1- N-carboxylate) (Compound 28)

Reference Example B26 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29)

Reference Example B27 Ethyl 6- [N- (4-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 30)

Reference Example B28 Ethyl 6- [N- (2,3,4-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 31)

Reference Example B29 Isobutyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 32)

Reference Example B30 Butyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 33)

Reference Example B31 Ethyl 6- [N- (4-bromo-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 34)

Reference Example B32 Ethyl 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 35)

Reference Example B33 Ethyl 6- [N- (2-acetoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 36)

Reference Example B34 Ethyl 6- [N- (3-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 37)

Reference Example B35 Ethyl 6- [N- (2,3-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 38)

Reference Example B36 Ethyl 6- [N- (2-ethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 39)

Reference Example B37 Ethyl 6- [N- [4- (2H-1,2,3-triazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 40)

Reference Example B38 Ethyl 6- [N- (2,5-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 41)

Reference Example B39 Ethyl 6- [N- (2-trifluoromethoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 42)

Reference Example B40 Ethyl 6- [N- (2,4,5-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 43)

Reference Example B41 Ethyl 6- [N- [4- (2H-tetrazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 44)

Reference Example B42 Ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl ] Cyclohex-1-ene-1-carboxylate) (Compound 45)

Reference Example B43 Ethyl 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 46)

Reference Example B44 Ethyl 6- [N- (2,6-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 47)

Reference Example B45 Ethyl 6- [N- [4- (1H-tetrazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 48)

Reference Example B46 Ethyl 6- [N- (4- (1H-1,2,3-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 49)

Reference Example B47 Ethyl 6- [N- (2-trifluoromethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 50)

Reference Example B48 Ethyl 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 51)

Reference Example B49 Benzyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 52)

Reference Example B50 Ethyl 6- [N- [4- [2,3-bis (tert-butoxycarbonyl) guanidinomethyl] phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 53 )

Reference Example B51 Ethyl 6- [N- (2-chloro-4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 54)

Reference Example B52 Ethyl 6- [N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 55)

Reference Example B53 2-hydroxyethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 56)

Reference Example B54 Ethyl 6- [N- [2-fluoro-4- (1H-1,2,4-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate ( Compound 57)

Reference Example B55 Ethyl 2- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 66)

Ethyl 5- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 58)

Reference Example B56 tert-butyl [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetate (Compound 59)

Reference Example B57 [6- [N- (2,4-Difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetic acid (Compound 60)

Reference Example B58 Ethyl 7- [N- (2,4-difluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 61)

Reference Example B59 Ethyl 6- [N- [2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 62)

Reference Example B60 Ethyl 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 63)

Reference Example B61 Ethyl 5- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (Compound 64)

Reference Example B62 2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -4,5,6,7-tetrahydro-1,2-benzisothiazole-3 ( 2H) -one 1,1-dioxide (Compound 69)

Reference Example B63 Ethyl 7- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 65)

Reference Example B64 2- (2,4-Difluorophenyl) -5,6,7,7a-tetrahydro-1,2-benzisothiazole 3 (2H) -one 1,1-dioxide (Compound 70 )

Reference Example B65 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29)

Reference Example B66 1-Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 71)

d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6- [N- (2-chloro-4 -Fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate) (compound 72)

Reference Example B67 Ethyl 6- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 73)

Reference Example B68 Ethyl 6- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 74)

Reference Example B69 High polar diastereomer (compound 75) and low polarity of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-carboxylate Diastereomers (Compound 76)

Reference Example B70 High polar diastereomer (compound 77) and low of ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-carboxylate Polar Diastereomers (Compound 78)

Reference Example B71 High polar diastereomers of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate (Compound 79) and Low Polar Diastereomers (Compound 80)

Reference Example B72 High polar diastereomers (compound 81) and low of ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-tert-butyl-cyclohexene-1-carboxylate Polar Diastereomers (Compound 82)

Reference Example B73 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 83)

Reference Example B74 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 84)

Reference Example B75 Ethyl 3-bromo-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 85).

Specific examples are shown in Tables 1-5 below.

TABLE 1-1

TABLE 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

TABLE 2

TABLE 3

Table 4-1

Table 4-2

TABLE 5

Reference example c mentioned below may be generated according to the reference example of WO01 / 10826, and reference example D may be generated according to the embodiment of WO01 / 10826.

Reference Example C

Reference Example C1

Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate in N, N-dimethylformamide (20 ml) (1 g, JP-A- Synthesized according to the method disclosed in 10-056492) and 1,8-diazabicyclo [5,4,0] -7-undecene (441 mg) in a solution of phenylmethanethiol (719 mg) under ice cooling. Dropwise, the mixture was stirred at rt for 18 h. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (70 ml x 2) and saturated brine (70 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by flash silica gel column chromatography (eluent: toluene) to give ethyl 6- (benzylsulfanyl) -1-cyclohexene-1-carboxylate (673 mg). Was obtained as a colorless oil.

Reference Example C2

In the same manner as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (1 g) and (4-methoxyphenyl Methanethiol (893 mg) was reacted to give ethyl 6-[(4-methoxybenzyl) -sulfanyl] -1-cyclohexene-1-carboxylate (848 mg) as a colorless oil.

Reference Example C3

In the same manner as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (455 mg) and (2,4-di Fluorophenyl) -methanethiol (421 mg) was reacted to give ethyl 6-[(2,4-difluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (185 mg) as a colorless oil. Obtained as.

Reference Example C4

In the same manner as in Reference Example C1, ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (835 mg) and (2-chloro- 4-Fluorophenyl) -methanethiol (853 mg) was reacted to ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (625 mg) Was obtained as a colorless oil.

Reference Example C5

3-pyranone (20.0 g) was prepared from Tetrahedron., Vol. 19, p. 1625 (1963)], to give ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (7.52 g) as a colorless oil.

Reference Example C6

Ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (12.9 g) was prepared from Tetrahedron., Vol. 30, p. 3753 (1974), to obtain ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (12.0 g) as light blue oil.

Elemental Analysis Value: As C ₈ H ₁₂ O ₃ S

Calculated value (%): C, 51.04; H, 6.43; S, 17.03.

Yield (%): C, 50.99; H, 6.54; S, 16.91.

Reference Example C7

Sodium peroxoborate tetrahydrate (24.5 g) was added to acetic acid (130 ml) and the mixture was heated to 50-55 ° C. Thereto, a solution of ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (10.0 g) in acetic acid (30 ml) was added dropwise over 2 hours (hr). The mixture was stirred at 50-55 ° C. for 3 hours, and the reaction mixture was concentrated under reduced pressure. Acetonitrile (230 ml) was added to the residue and the mixture was stirred at room temperature for 2 hours, the resulting insoluble material was removed by filtration and washed with acetonitrile (70 ml). The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and the mixture was stirred at rt for 6 h. The resulting insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue, diisopropyl ether (100 ml) was added, and the precipitated insoluble material was filtered off to yield 4- (ethoxycarbonyl) -5,6-dihydro-2H-pyran-3-sulfonic acid insoluble product. Obtained as a pale yellow oil (27.6 g) containing.

Reference Example C8

4- (ethoxycarbonyl) -5,6-dihydro-2H-pyran-3-sulfuric acid (27.5 g) is dissolved in thionyl chloride (82.6 ml) and the mixture is stirred at room temperature-> 85 &lt; 0 &gt; C Stir for hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). The resulting solution was partitioned by adding dilute brine (120 ml). The ethyl acetate layer was washed twice with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/7-> 1/5). The desired product was concentrated under reduced pressure, and the crystals produced by freezing were washed with hexane to give ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (7.81 g). Obtained as pale yellow crystals.

Elemental Analysis Value: As C ₈ H ₁₁ ClO ₅ S

Calculated value (%): C, 37.73; H, 4.35.

Yield (%): C, 37.64; H, 4.27.

Reference Example D

Reference Example D1

To a solution of ethyl 6- (benzylsulfanyl) -1-cyclohexene-1-carboxylate (100 mg) obtained in Reference Example C1 in methylene chloride (3 ml), m-chlorobenzoic acid (196 mg) under ice cooling ) Was added and the mixture was stirred at rt for 1 h. To the reaction solution, saturated aqueous sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted with ethyl acetate (20 ml x 2). The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water (20 ml) and saturated brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue obtained was purified by flash silica gel chromatography (eluent: hexane-> ethyl acetate / hexane = 1/30), crystallized from hexane, ethyl 6- (benzylsulfonyl)- 1-cyclohexene-1-carboxylate (Compound 86, 106 mg) was obtained as white crystals.

Elemental Analysis Value: As C ₁₆ H ₂₀ O ₄ S.0.5H ₂ O

Calculated value (%): C, 60.55; H, 6.67

Yield (%): C, 60.98; H, 6.32.

Reference Example D2

In the same manner as in Reference Example D1, ethyl 6-[(4-methoxybenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (98 mg) obtained in Reference Example C2 was reacted to give ethyl 6 -[(4-methoxybenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 87, 88 mg) was obtained as white crystals.

Elemental Analysis Value: As C ₁₇ H ₂₂ O ₅ S

Calculated (%): C, 60.33; H, 6.55

Yield (%): C, 60.42; H, 6.58.

Reference Example D3

In the same manner as in Reference Example D1, ethyl 6-[(2,4-difluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (161 mg) obtained in Reference Example C3 was reacted to react. , Ethyl 6-[(2,4-difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 88, 134 mg) was obtained as white crystals.

Elemental analysis value: As C ₁₆ H ₁₈ F ₂ O ₄ S

Calculated value (%): C, 55.80; H, 5.27

Yield (%): C, 55.95; H, 5.40.

Reference Example D4

In the same manner as in Reference Example D1, ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (509 mg) obtained in Reference Example C4 was reacted. To give ethyl 6-[(2-chloro-4-fluorobenzyl) -sulfonyl] -1-cyclohexene-1-carboxylate (compound 89, 422 mg) as white crystals.

Elemental Analysis Value: As C ₁₆ H ₁₈ ClFO ₄ S

Calculated value (%): C, 53.26; H, 5.03

Yield (%): C, 53.08; H, 4.95.

Reference Example D5

Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 89, 100 mg) obtained in Reference Example D4 was subjected to high performance liquid chromatography (CHIRALPAK AD). Eluent: hexane / ethanol 8/2), dissolved in two enantiomers. The eluate was filtered through a 0.45 μm filter, concentrated and crystallized from hexanes to give ethyl (-)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1- Carboxylate (compound 90, 50 mg) and ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 91, 49 mg ) Were each obtained as white crystals.

Compound 90

Elemental Analysis Value: As C ₁₆ H ₁₈ ClFO ₄ S

Calculated value (%): C, 53.26; H, 5.03

Yield (%): C, 53.24; H, 4.85.

[α] _D ²⁰ -97.0 ° (c = 0.5 in methanol).

Compound 91

Elemental Analysis Value: As C ₁₆ H ₁₈ ClFO ₄ S

Calculated (%): C, 53.26; H, 5.03

Obtained (%): C, 53.29; H, 4.82.

[α] _D ²⁰ + 95.0 ° (c = 0.5, in methanol).

Reference Example D6

2,4-difluoroaniline (0.45 g) was dissolved in ethyl acetate (10 ml) and triethylamine (0.55 mg) was added to the solution obtained under ice cooling. Next, a solution of ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (0.69 g) obtained in Reference Example C8 in ethyl acetate (4 ml) was added dropwise. The reaction mixture was stirred under nitrogen stream at 0 ° C. for 30 minutes and at room temperature for 5.8 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water (50 ml), 0.5N hydrochloric acid (50 ml), water (50 ml x 2) and saturated brine (50 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / hexane = 1/2). The desired fractions were concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 3-[(2,4-difluorophenyl) -sulfamoyl] -3,6-dihydro- 2H-pyran-4-carboxylate (compound 92; 0.57 g) was obtained as white crystals.

Elemental Analysis Value: As C ₁₄ H ₁₅ F ₂ NO ₅ S

Calculated value (%): C, 48.41; H, 4.35; N, 4.03.

Yield (%): C, 48.47; H, 4.35; N, 3.96

Reference Example D7

In the same manner as in Reference Example D6, ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (0.70 g) obtained in Reference Example C8 was substituted with 2-chloro-4 Reacted with -fluoroaniline (0.52 g) to yield ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (Compound 93 0.54 g) was obtained as white crystals.

Elemental Analysis Value: As C ₁₄ H ₁₅ ClFNO ₅ S

Calculated value (%): C, 46.22; H, 4.16; N, 3.85.

Yield (%): C, 46.35; H, 4.11; N, 3.73.

Specific examples of the compounds of the present invention that can be synthesized in the same manner as in the above-referenced examples are shown in Tables 6 and 7. However, the present invention is not limited to the compounds exemplarily shown in Tables 6 and 7.

TABLE 6

TABLE 7

Example 1

Formulation 1 Comparative Formulation 2 Compound 72 11 g 17 g Soybean oil 220 g 340 g Egg yolk lecithin 13.2 g 20.4 g glycerin 24.7 g 38.25 g Dimyristoylphosphatidylglycerol 2.2 g 3.4 g Glacial acetic acid 11.2 mM - Sodium Acetate Anhydrous 8.8 mM - Total amount of distilled water 1.1 L 1.7 L

11 g of compound 72 was dissolved in 220 g of soybean oil, and 13.2 g of egg yolk lecithin and 2.2 g of dimyristoylphosphatidylglycerol were further dissolved. 24.7 g of glycerin was dissolved in distilled water, the acetate buffer was mixed and dissolved, and the final concentrations were 11.2 mM acetic acid and 8.8 mM sodium acetate. These were mixed, approximately emulsified and then finely emulsified at 8000 psi pressure using a high pressure homogenizer. The obtained emulsion composition was filled in 20 mL vials each 20 mL. After nitrogen substitution, the vial was tightly sealed with a rubber stopper and a plastic cap. The composition was sterilized in an autoclave at 121 ° C. or higher for at least 15 minutes to obtain an emulsified composition having the aforementioned composition of Formulation 1.

Next, for comparison, 17 g of compound 72 was dissolved in 340 g of soybean oil, and 20.4 g of egg yolk lecithin and 3.4 g of dimyristoylphosphatidylglycerol were further dissolved. 38.25 g of glycerin was dissolved in distilled water. These were mixed, approximately emulsified and then finely emulsified at 8000 psi pressure using a high pressure homogenizer. The obtained emulsion composition was filled in 20 mL vials each 20 mL. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap. The composition was sterilized in an autoclave at 121 ° C. or higher for at least 15 minutes to obtain an emulsion composition having the above-mentioned composition of Comparative Formula 2.

Example 2

The emulsion composition of Comparative Example 1 and Comparative Formulation 2 obtained in Example 1 were stored at 25 ° C. and their appearance, pH value and average particle size were measured at timed intervals. Particle size was measured by Malvern Mastersizer S.

The results are shown in Table 8.

In Formulation 1 containing acetate buffer, the pH value remained almost unchanged before and after sterilization and upon prolonged storage at 25 ° C., Formulation 1 had a stable appearance, pH value, and average particle size. However, in Comparative Formulation 2, the pH value decreased from 4.6 to 4.0 before and after sterilization and further decreased to 3.6 when stored at 25 ° C. for 3 months. According to the decrease in pH value, the instability of the emulsion composition occurred. When the composition was stored at 25 ° C. for 6 months, the appearance became inadequate because the dispersed phase particles and the water in which the dispersed phase particles were dispersed phase separated and thus the average particle size increased to 0.8 μm. . The addition of acetate buffer to the emulsion composition containing compound 72 has made it possible to improve the decrease in pH value upon sterilization or long term storage.

TABLE 8

ocean pH Average particle size (μm) Formulation 1 Before sterilization app ^{1 )} 4.4 0.3 Early app 4.4 0.3 3 months at 25 ℃ app 4.4 0.3 6 months at 25 ℃ app 4.5 0.3 Comparative Formulation 2 Before sterilization app 4.6 0.3 Early app 4.0 0.3 3 months at 25 ℃ app 3.6 0.3 6 months at 25 ℃ inapp ^{2 )} 3.6 0.8 app: appropriate inapp: inadequate 1) Free oil droplets, creaming and phase separation were not observed. 2) The dispersed phase particles and the water in which the dispersed phase particles were dispersed were phase separated.

Example 3

Formulation 3 Comparative Formulation 4 Compound 72 600 g 600 g Soybean oil 12000 g 12000 g Egg yolk lecithin 720 g 720 g glycerin 1350 g 1350 g Dimyristoylphosphatidylglycerol 120 g 120 g Glacial acetic acid 40.35 g - Sodium acetate trihydrate 71.85 g - Total amount of distilled water 60 L 60 L

600 g of Compound 72 were dissolved in 12 kg of soybean oil, and 720 g of purified yolk lecithin and 120 g of dimyristoylphosphatidylglycerol were further dissolved at 50 to 60 ° C. 1350 g of glycerin was dissolved in 20 kg of distilled water, 40.35 g of glacial acetic acid and 71.85 g of sodium acetate trihydrate were mixed and dissolved at 50 to 60 ° C. These were then mixed and distilled water was added to bring the total amount to 60 L, approximately emulsified for 5 minutes using a homogenizer Polytron, and finely homogenized at 8000 psi pressure and 8-pass conditions using a high pressure homogenizer. . Dissolution and emulsification of compound 72 was carried out under a nitrogen gas stream. The obtained emulsion composition was passed through a membrane filter having a pore size of 4.5 μm, and 20 mL were filled in 20 mL vials. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap. The composition was sterilized in an autoclave at 121 ° C. for at least 15 minutes to yield an emulsion composition formulation 3 having the composition described above.

Next, for comparison, 600 g of Compound 72 was dissolved in 12 kg of soybean oil, and 720 g of purified yolk lecithin and 120 g of dimyristoylphosphatidylglycerol were further dissolved at 50 to 60 ° C. 1350 g of glycerin were mixed and dissolved in 35 kg of distilled water at 50 to 60 ° C. Then they were mixed and distilled water was added to bring the total amount to 60 L and approximately emulsified for 5 minutes using a homogenizer Polytron.

They were then finely emulsified at 8000 psi pressure and 8-pass conditions using a high pressure homogenizer. Dissolution and emulsification of compound 72 was carried out under a nitrogen gas stream. The emulsion composition obtained was passed through a membrane filter with a pore size of 5 μm and filled in 20 mL vials of 20 mL. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap. The composition was sterilized at 121 ° C. for at least 15 minutes in an autoclave to give Comparative Emulsifying Composition Formulation 4 having the composition described above.

Example 4

The emulsified composition and Comparative Formulation 4 of Formulation 3 obtained in Example 3 were stored at 25 ° C. and their appearance, pH value and average particle size were measured over time. The mean particle size of Formulation 3 was measured by Malvern Mastersizer 2000 and the mean particle size of Comparative Formulation 4 was measured by Malvern Mastersizer S.

The results are shown in Table 9. In Formulation 3 containing acetate buffer, the pH value was stable before and after emulsification-sterilization, the pH value did not decrease even after long term storage at 25 ° C., and also the appearance and average particle size did not change, 3 was highly stable.

However, in Comparative Formulation 4, after 3 months of storage at 25 ° C., the pH value decreased and the appearance became inadequate because free oil droplets were present on the surface of the emulsion composition, and the average particle size was 25 ° C. After storage for 6 months at, it increased to 3.6 μm. Thus, an emulsion composition in which the pH value was not reduced upon preparation, sterilization, and long term storage could be obtained by adding 20 mM acetate buffer to the emulsion composition containing compound 72. In this way, it has become possible to produce emulsion compositions with high stability.

TABLE 9

ocean pH Average particle size (μm) Formulation 3 Oil painting-sterile ex app1 ⁾ 4.5 - Early app 4.4 0.2 3 months at 25 ℃ app 4.5 0.2 6 months at 25 ℃ app 4.5 0.2 15 months at 25 ℃ app 4.5 0.2 18 months at 25 ℃ app 4.5 0.2 24 months at 25 ℃ app 4.5 0.2 Comparative Formulation 4 Sterilization-Before Sterilization app 5.2 - Early app 4.0 0.3 3 months at 25 ℃ app 3.5 0.3 6 months at 25 ℃ inapp ^{2 )} 3.5 3.6 app: appropriate inapp: inadequate 1) Free oil droplets, creaming and phase separation were not observed. 2) Free oil droplets were visually observed.

Example 5

To prepare formulations containing various types of buffers in a total ratio of 25 mL in the same ratio as Comparative Formulation 2, various concentrations of buffers were added and dissolved in an aqueous phase consisting of glyserine and distilled water. The composition of each buffer is acetic acid and sodium acetate in acetate buffer, lactic acid and sodium lactate in lactate buffer, citric acid and sodium citrate in citrate buffer, disodium hydrogenphosphate and citric acid in phosphate-citrate buffer, phosphate buffer Sodium monodihydrogen phosphate and disodium hydrogenphosphate, and sodium carbonate and sodium hydrogencarbonate in carbonate buffer and these were added at the concentrations described in Tables 10-13. Compound 72, egg yolk lecithin and dimyristoylphosphatidylglycerol were then dissolved in soybean oil. These were mixed, approximately emulsified with a homogenizer, and then an emulsion composition was prepared by Sonicator. The emulsion composition obtained was passed through a membrane filter with a pore size of 5 μm and filled in 20 mL vials of 20 mL. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap and sterilized in an autoclave at 121 ° C. for at least 15 minutes to obtain an emulsion composition with various types of buffer added. Each pH value of the emulsion composition was tested before and after treatment in the autoclave.

The results are shown in Tables 10-13. 5 mM to 32 mM acetate buffer, lactate buffer, citrate buffer and phosphate-citrate buffer are added to an emulsified composition consisting of compound 72 to emulsify the pH 4-5 and change pH little by high pressure steam sterilization. A composition was obtained.

In addition, when the pH value of the emulsion composition was adjusted to 6 by adding a liquid buffer, even when phosphate buffer, carbonate buffer and citrate buffer were used, the pH value was significantly reduced by high pressure steam sterilization. Using carbonate buffer, the pH value was changed to about 7 before autoclaving.

TABLE 10

PH value of emulsion composition Type of buffer Concentration of buffer High Pressure Steam Sterilization pH 4 Acetate buffer 5 mM Before treatment 4.1 After treatment 4.1 10 mM Before treatment 4.0 After treatment 4.0 15 mM Before treatment 4.0 After treatment 4.0 20 mM Before treatment 4.0 After treatment 4.0 Lactate buffer 5 mM Before treatment 4.2 After treatment 4.1 12.5 mM Before treatment 4.2 After treatment 4.1 25 mM Before treatment 4.2 After treatment 4.1 Citrate buffer 5 mM Before treatment 4.1 After treatment 4.1 10 mM Before treatment 4.0 After treatment 4.1 15 mM Before treatment 4.0 After treatment 4.1 20 mM Before treatment 4.1 After treatment 4.2

TABLE 11

PH value of emulsion composition Type of buffer Concentration of buffer High Pressure Steam Sterilization pH 4.5 Acetate buffer 5 mM Before treatment 4.6 After treatment 4.5 10 mM Before treatment 4.6 After treatment 4.4 15 mM Before treatment 4.5 After treatment 4.4 20 mM Before treatment 4.5 After treatment 4.4 Lactate buffer 5 mM Before treatment 4.5 After treatment 4.4 12.5 mM Before treatment 4.5 After treatment 4.4 25 mM Before treatment 4.5 After treatment 4.4 Phosphate-citrate buffer 8 mM Before treatment 4.7 After treatment 4.3 16 mM Before treatment 4.6 After treatment 4.3 32 mM Before treatment 4.6 After treatment 4.3 Citrate buffer 5 mM Before treatment 4.6 After treatment 4.7 10 mM Before treatment 4.6 After treatment 4.7 15 mM Before treatment 4.5 After treatment 4.7 20 mM Before treatment 4.5 After treatment 4.7

TABLE 12

PH value of emulsion composition Type of buffer Concentration of buffer High Pressure Steam Sterilization pH 5 Acetate buffer 5 mM Before treatment 5.0 After treatment 4.8 10 mM Before treatment 5.0 After treatment 4.8 15 mM Before treatment 4.9 After treatment 4.8 20 mM Before treatment 5.0 After treatment 4.9 Citrate buffer 5 mM Before treatment 5.1 After treatment 5.1 10 mM Before treatment 5.1 After treatment 5.2 15 mM Before treatment 5.1 After treatment 5.1 20 mM Before treatment 5.0 After treatment 5.0

TABLE 13

PH value of emulsion composition Type of buffer Concentration of buffer High Pressure Steam Sterilization pH 6 Citrate buffer 5 mM Before treatment 6.3 After treatment 5.6 10 mM Before treatment 6.3 After treatment 5.7 15 mM Before treatment 6.3 After treatment 5.7 20 mM Before treatment 6.3 After treatment 5.6 Phosphate buffer 5 mM Before treatment 6.1 After treatment 4.6 10 mM Before treatment 6.1 After treatment 4.7 15 mM Before treatment 6.0 After treatment 5.0 20 mM Before treatment 6.0 After treatment 5.3 Carbonate buffer 5 mM Before treatment 7.0 After treatment 4.3 10 mM Before treatment 7.0 After treatment 4.3 15 mM Before treatment 7.0 After treatment 5.0 20 mM Before treatment 7.1 After treatment 5.6

Example 6

Formulation 5 Compound 72 500 g Soybean oil 10000 g Egg yolk lecithin 600 g glycerin 1125 g Dimyristoylphosphatidylglycerol 100 g Glacial acetic acid 33.63 g Sodium acetate trihydrate 59.88 g Total amount of distilled water 50 L

500 g of Compound 72 were dissolved in 10 kg of soybean oil, and 600 g of purified yolk lecithin and 100 g of dimyristoylphosphatidylglycerol were further dissolved at 50 to 55 ° C. 1125 g of glycerin was dissolved in about 10 kg of distilled water, and 33.63 g of glacial acetic acid and 59.88 g of sodium acetate trihydrate were dissolved at 50 to 55 ° C. They were then mixed and distilled water was added to bring the total amount to 50 L, approximately emulsified and finely emulsified at 8000 psi pressure and 8-pass conditions using a high pressure homogenizer. Dissolution and emulsification of compound 72 was carried out under a nitrogen gas stream. The emulsion composition obtained was passed through a membrane filter with a pore size of 4.5 μm and filled in 20 mL vials of 20 mL. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap. Similarly, the obtained emulsion composition was filled with 10 mL in 20 mL vials, 5 mL in 20 mL vials, 10 mL in 10 mL vials, and 5 mL in 5 mL vials, followed by nitrogen replacement. The composition was tightly sealed with a rubber stopper and a plastic cap. These compositions were sterilized in an autoclave at 121 ° C. for at least 15 minutes to obtain an emulsion composition of Formulation 5 having the above-described composition and different vial sizes and fills.

Example 7

The pH value and average particle size of the emulsion composition of Formulation 5 obtained in Example 6 were measured before and after the autoclave treatment. Particle size was measured by Malvern Mastersizer 2000.

The results are shown in Table 14.

In Formulation 5 containing acetate buffer, regardless of the vial size and fill amount, the pH value was constant and the mean particle size did not change before and after sterilization, thus Formulation 5 was very stable.

TABLE 14

Vial size Charge High Pressure Steam Sterilization pH Average particle size (μm) Formulation 5 20 mL 20 mL Before treatment 4.6 0.2 After treatment 4.6 0.2 20 mL 10 mL Before treatment 4.6 0.2 After treatment 4.5 0.2 20 mL 5 mL Before treatment 4.6 0.2 After treatment 4.6 0.2 10 mL 10 mL Before treatment 4.6 0.2 After treatment 4.6 0.2 5 mL 5 mL Before treatment 4.6 0.2 After treatment 4.6 0.2

Example 8

Formulation 5 Compound 72 5000 g Soybean oil 100000 g Egg yolk lecithin 6000 g glycerin 11250 g Dimyristoylphosphatidylglycerol 1000 g Glacial acetic acid 336.3 g Sodium acetate trihydrate 598.8 g Total amount of distilled water 500 L

5000 g of compound 72 were dissolved in 100 kg of soybean oil, and 6000 g of purified egg yolk lecithin and 1000 g of dimyristoylphosphatidylglycerol were further dissolved at 50 to 55 ° C. 11250 g of glycerin was dissolved in distilled water, and 336.3 g of glacial acetic acid and 598.8 g of sodium acetate trihydrate were dissolved at 50 to 55 ° C. They were then mixed and distilled water was added to bring the total amount to 500 L, approximately emulsified, and finely emulsified at 8000 psi pressure and 8-pass conditions using a high pressure homogenizer. Dissolution and emulsification of compound 72 was carried out under a nitrogen gas stream. The emulsified composition obtained was passed through a membrane filter with a pore size of 4.5 μm, filled with 10 mL in 10 mL vials and 5 mL in 10 mL vials. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap. These compositions were sterilized in an autoclave at 121 ° C. for at least 15 minutes to obtain an emulsified composition of Formulation 6 having the above-described composition and different fill amounts.

Example 9

The pH value and average particle size of the emulsion composition of Formulation 6 obtained in Example 8 were measured before and after autoclave treatment. Particle size was measured by Malvern Mastersizer 2000.

The results are shown in Table 15.

In Formulation 6 containing acetate buffer, regardless of the amount charged, the pH value was constant before and after sterilization and the mean particle size did not change, making Formulation 6 very stable.

TABLE 15

Vial size Charge High Pressure Steam Sterilization pH Average particle size (μm) Formulation 6 10 mL 10 mL Before treatment 4.6 0.2 After treatment 4.5 0.2 10 mL 5 mL Before treatment 4.6 0.2 After treatment 4.5 0.2

Comparative Example 1

To prepare a formulation with a total volume of 25 mL, containing various concentrations of sodium hydroxide as pH adjusters in the same ratio as in Comparative Example 2, each was dissolved in an aqueous phase consisting of glycerin and distilled water to give a final concentration of sodium hydroxide at 0, Made to 0.5, 0.75, 1, 1.5 and 2.0 mM. Compound 72, egg yolk lecithin and dimyristoylphosphatidylglycerol were then dissolved in soybean oil. These were mixed, approximately emulsified using a homogenizer, and then an emulsion composition was prepared by Sonicator. The emulsion composition obtained was passed through a membrane filter with a pore size of 5 μm and filled in 20 mL vials of 20 mL. After nitrogen substitution, the composition was tightly sealed with a rubber stopper and a plastic cap and sterilized for at least 15 minutes in an autoclave at 121 ° C. to obtain an emulsion composition in which sodium hydroxide with various concentrations was added as a pH adjuster. Each pH value of the emulsion composition was tested before and after treatment in the autoclave.

The results are shown in Table 16. Both emulsion compositions with or without Compound 72 significantly lowered the pH value after sterilization when all concentrations of sodium hydroxide were added.

TABLE 16

Sodium hydroxide concentration High Pressure Steam Sterilization pH 0 mM Before treatment 5.4 After treatment 4.6 0.5 mM Before treatment 6.5 After treatment 4.5 0.75 mM Before treatment 6.7 After treatment 4.5 1 mM Before treatment 6.7 After treatment 4.5 1.5 mM Before treatment 6.7 After treatment 4.6 2.0 mM Before treatment 6.9 After treatment 4.7

[Industrial Availability]

As is evident from the foregoing detailed description, the emulsion composition of the present invention is adjusted to a pH of about 3.7 to about pH 5.5 by adding a buffer. Therefore, the pH of the emulsion composition and the average particle size of the dispersed phase particles therein hardly change after sterilization in an autoclave or the like or even after long term storage, and the composition is stable. As a result, the emulsion compositions of the present invention and their compounds, salts or prodrugs thereof, which are the active ingredients of the emulsion compositions, exhibit excellent stability. Moreover, sterilization and long term preservation of the emulsion composition of the present invention in an autoclave or the like does not produce visible observable droplets of free oil. That is, the dispersed phase particles and the water in which the dispersed phase particles are dispersed do not exhibit phase separation and are stable.

In addition, the emulsion composition of the present invention can be adjusted to a pH of about 3.7 to about 5.5 by adding a buffer, so that a stable emulsion composition is obtained, and the optimum pH can be determined according to various other conditions such as the characteristics of the emulsifier and the stability of the compound, and the like. have. Thus, even when other conditions exist that can be overcome by adjusting the pH to about 3.7 to about 5.5, such as when the stability of the emulsion composition is affected, etc., an emulsion composition that satisfies various conditions is obtained by pH adjustment. Can be

Moreover, the emulsion composition of the present invention shows long term storage stability for 24 hours. This is in excess of 18 months, which is the general duration of use of emulsified formulations.

This application is based on the patent application No. 2005-131807 for which it applied in Japan, The content is taken in here as a reference.

Claims (29)

As an emulsifying composition comprising: (A) a compound stable in the acidic range, and (B) a buffer, Wherein the pH is adjusted to between about 3.7 and about 5.5. The composition of claim 1 further comprising an anionic synthetic phospholipid as emulsifier. The composition of claim 1 or 2, wherein (A) the compound stable in the acidic range is (a) or (b), or a salt thereof or a prodrug thereof: (a) a compound of formula (I)

[Wherein R is Optionally substituted aliphatic hydrocarbon groups, Optionally substituted aromatic hydrocarbon groups, Optionally substituted heterocyclic group, A group represented by the formula: -OR ^1, wherein R ¹ represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, Or a group represented by the following formula:

(Wherein, R ^1b represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, and R ^1c represents R ^1b The same as or different from and represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), R ⁰ represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or Or R and R ⁰ come together to form a bond, Ring A ¹ is cycloalkene optionally substituted with 1 to 4 substituents selected from the group consisting of: (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) a chemical formula: -OR ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group optionally having a substituent), and (4) halogen atoms, Ar represents an optionally substituted aromatic hydrocarbon group, The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the following formula:

n represents an integer of 1 to 4; (b) a compound of formula (II)

[Wherein, R ^{1 ′} is Optionally substituted aliphatic hydrocarbon groups, Optionally substituted aromatic hydrocarbon groups, Optionally substituted heterocyclic group, A group represented by the formula -OR ^{1a '} wherein R ^1a' represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, Or a group represented by the following formula:

In which R ^{1b '} And R ^{1c ′} Are the same as or different from each other, and represent a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), X represents a methylene group, a nitrogen atom, a sulfur atom, or an oxygen atom, Y represents an optionally substituted methylene group or an optionally substituted nitrogen atom, Ring A is a 5-8 membered ring optionally further substituted by 1-4 substituents selected from the group consisting of: (1) an aliphatic hydrocarbon group optionally having a substituent, (2) an aromatic hydrocarbon group optionally having a substituent, (3) a group represented by the formula: OR ^{2 '} (wherein R ^2' represents an aliphatic hydrocarbon group optionally having a hydrogen atom or a substituent), and (4) halogen atoms, Ar 'represents an optionally substituted aromatic hydrocarbon group, The group represented by the following formula:

A group represented by the following formula:

Or a group represented by the following formula:

, m represents an integer of 0 to 2, n 'represents an integer of 1 to 3, the sum of m and n 'is 4 or less, Provided that when X is a methylene group, Y represents an optionally substituted methylene group. 4. A compound according to claim 3, wherein the compound represented by formula (I) is (6R) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate, ethyl 6- [N- (2-chlorophenyl) sulfamoyl] cyclo A composition selected from the group consisting of hex-1-ene-1-carboxylate or ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate. The composition of claim 1 or 2, wherein the buffer is one or two or more buffers selected from the group consisting of acetate buffers, lactate buffers, citrate buffers, and phosphate buffers. 6. The composition of claim 5 wherein the acetate buffer is acetic acid and sodium acetate. The emulsion composition according to claim 1 or 2, wherein the buffer concentration is 100 mM or less. The composition of claim 1 further comprising a component selected from the group consisting of oils, emulsifiers, water and combinations thereof. The composition of claim 8 which is of oil-in-water type. The composition according to claim 1 or 2, comprising dispersed phase particles comprising a compound, an oil, and an emulsifier, which are stable in an acidic range, and water in which the dispersed phase particles are dispersed. The composition of claim 10 wherein the mean particle size of the dispersed phase particles is from about 0.025 to about 0.7 μm. The composition according to claim 10, wherein the dispersed phase particles and the water in which the dispersed phase particles are dispersed are stable without phase separation. 10. The composition of claim 9, which contains no visible oil droplets. The composition of claim 8 wherein the oil is vegetable oil. The composition of claim 14 wherein the vegetable oil is soybean oil. The composition of claim 8 wherein the emulsifier is a phospholipid. The composition of claim 16 wherein the phospholipid is egg yolk lecithin or phosphatidylglycerol. The composition of claim 2 wherein the anionic synthetic phospholipid is phosphatidylglycerol. The composition of claim 8, wherein the oil is in a fraction of about 1 to about 30 weight percent of the total composition. The composition of claim 8 wherein the emulsifier is in a fraction of about 0.1 to about 10% (W / V) of the total composition. 19. The composition of claim 17 or 18, wherein the phosphatidylglycerol is dimyristoylphosphatidylglycerol. 9. The composition of claim 8 further comprising soybean oil, egg yolk lecithin, glycerin and water. A composition according to claim 1 or 2 for injection. 3. The composition of claim 1 or 2, wherein the compound that is stable in the acidic range is at a fraction of about 0.001 to about 95 weight percent of the total composition. A process for preparing an emulsion composition comprising (A) a compound stable in the acidic range and (B) a buffer comprising adjusting the pH of the emulsion composition to a range of about 3.7 to about 5.5. The method of claim 25, wherein the emulsion composition further comprises an anionic synthetic phospholipid as an emulsifier. The method of claim 25, wherein the stability of the pH of the emulsion composition and the particle size of the dispersed phase particles is improved during autoclave sterilization. Adjusting the pH of the emulsifying composition to a range of about 3.7 to about 5.5; a method for stabilizing an emulsion composition comprising (A) a compound stable in the acidic range and (B) a buffer. The method of claim 28 further comprising adding an anionic synthetic phospholipid as an emulsifier to the emulsion composition.